Modernizing Schizophrenia Care:Pharmacotherapy Innovations and

Clinical Implications

Leslie Citrome, MD, MPHClinical Professor of Psychiatry and Behavioral SciencesNew York Medical CollegeValhalla, New York

Professor of Psychiatry and Molecular MedicineHofstra Northwell School of MedicineHempstead, New YorkInvestigator, Center for Psychiatric NeuroscienceFeinstein Institute for Medical ResearchManhasset, New YorkMedical Director, Recognition and Prevention ProgramThe Zucker Hillside Hospital, Department of Psychiatry

Christoph U. Correll, MD

This activity is supported by an educational grant from Alkermes, Inc.

Faculty Disclosure

• Dr. Citrome: Consultant—Acadia, Alkermes, Allergan, Intra-Cellular Therapeutics, Janssen, Lundbeck, Merck, Neurocrine, Noven, Osmotica, Otsuka, Pfizer, Shire, Sunovion, Takeda, Teva, Vanda; Royalties—Springer Healthcare (book), UpToDate(reviewer), Wiley (Editor in Chief, International Journal of Clinical Practice); Shareholder (and spouse)—Bristol-Myers Squibb, Eli Lilly, J & J, Merck, Pfizer; Speaker—Acadia, Alkermes, Allergan, Janssen, Lundbeck, Merck, Neurocrine, Otsuka, Pfizer, Shire, Sunovion, Takeda, Teva.

• Dr. Correll: Consultant—Alkermes, Allergan, Angelini, Boehringer-Ingelheim, Gedeon Richter, Gerson Lehrman Group, Indivior, IntraCellular Therapies, Janssen/J&J, LB Pharmaceuticals, Lundbeck, MedAvante-ProPhase, Medscape, Merck, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, Teva; Expert Testimony—Bristol-Myers Squibb, Janssen, Otsuka; Royalties—UpToDate; Grant Support—Janssen, Takeda; Shareholder—LB Pharmaceuticals.

Disclosure

• The faculty have been informed of their responsibility to disclose to the audience if they will be discussing off-label or investigational use(s) of drugs, products, and/or devices (any use not approved by the US Food and Drug Administration).

• Applicable CME staff have no relationships to disclose relating to the subject matter of this activity.

• This activity has been independently reviewed for balance.

Learning Objectives• Understand the mechanisms of action and formulations of available

and emerging antipsychotics with respect to their specific clinical application in terms of efficacy, safety, and adherence

• Identify the factors contributing to medication nonadherence and develop strategies to recognize, overcome, and prevent long-term non-engagement

• Acquire effective patient-centered approaches to effective communication strategies that promote patient engagement through shared-decision making

• Evaluate clinical evidence and patient-specific symptomology, comorbidities, obstacles, and preferences to formulate an individualized team-based, optimized treatment plan

Meet Roger

• Roger was diagnosed with schizophrenia at age 18 years in the era of first-generation antipsychotics and has received haloperidol for many years; he is currently on haloperidol decanoate

• Now he is 55 years old, and remains symptomatic with auditory hallucinations, which he is usually able to ignore

• Roger is uninterested in doing much in the way of physical activities, and spends most of the day sitting in the living room of his shared supervised residence; he has no complaints other than new restrictions on when and where he can smoke his cigarettes

• Roger’s BMI is 29.6 kg/m2 and his fasting blood glucose is 105 mg/dL

• Roger has mild drug-induced parkinsonism and has developed some mild dyskinetic movements of his tongue

BMI = body mass index.

Characteristics of Available and Emerging Antipsychotics

What is different and what is new that we can offer Roger? Are all the antipsychotics the same in terms of efficacy?

What about side effects? What about LAI antipsychotics?

What is being developed as we speak?

Network Meta-Analysis of Antipsychotics for the Acute Rx of Multi-episode Adults with Schizophrenia

Aim• Create hierarchy for 32 APs• 17 outcomes (8 efficacy and 9 major

side-effect outcomes)• Direct and indirect comparisonsData set• 402 RCTs • Acute schizophrenia• 53,463 participants• Mean age: 37.4 years• Males: 56.0%• Mean illness duration: 11.9 ± 5.2 years• Trial duration: 3 to 13 weeks

AP = antipsychotic; RCT = randomized controlled trial.Huhn M, et al. Lancet. 2019;394(10202):939-951.

Network of Comparisons for Efficacy

SMD = standardized mean difference; CrI = credible interval.Huhn M, et al. Lancet. 2019;394(10202):939-951.

Network Meta-Analysis of Antipsychotics for SchizophreniaOverall Symptom Change: Other than Clozapine, No Clear “Winner”

Level of confidence in the evidence:

EPS = extrapyramidal symptoms. Huhn M, et al. Lancet. 2019;394(10202):939-951.

Side Effects are Different! EPS, Akathisia, Prolactin

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

Side Effects are Different! Weight Gain, Sedation, QTc

What is the potential role for LAI antipsychotics in reducing relapse or hospitalizations? Depends how you look!

LAI = long-acting injectable; RR = risk ratio.Kirson NY, et al. J Clin Psychiatry. 2013;74(6):568-575.

2.0

1.8

1.6

1.4

1.2

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0.8

0.6

0.4

0.2

Randomized Clinical Studies

2.2

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ted

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ProspectiveStudies

RetrospectiveStudies

RR=0.622RR=0.877

RR=0.558

RCT Real-world

As study design shifts toward real-world populations, LAI formulations display

significant advantages

Fa

vors

O

ral

Fa

vors

LA

I

RelapseHospitalizationAll-cause discontinuationOverall

Adverse Effects with LAI vs Same Oral AntipsychoticsNo Difference in Frequency of at Least 1 Adverse Effect

• Out of all 119 adverse events, LAIs and OAPs did not differ significantly regarding 115 (96.6%)• LAIs were associated with more akinesia, low-density lipoprotein cholesterol change, and anxiety• LAIs were associated with significantly lower prolactin change

N=16, n=4902. OAP = oral antipsychotic. Misawa F, et al. Schizophr Res. 2016;176(2-3):220-230.

Agents in Development for Total Symptoms of Schizophrenia

AMPA = alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CGI-I = Clinical Global Impression-Improvement; CGI-S = Clinical Global Impression-Severity; GAF = Global Assessment of Functioning Scale; NMDA = N-methyl-D-aspartate; PANSS = Positive and Negative Syndrome Scale.Adapted from: Krogmann A, et al. CNS Spectrums. 2019;24(Suppl 1):38-69.

Treatment Company Phase Mechanism of Action Results

Cannabidiol(add-on)

N/A N/APartial cannabinoid1 receptor antagonist, calcium channel

modulator

Superior vs placebo: PANSS positive, CGI-I/S

Not superior: PANSS total, negative and general subscale scores, GAF

F17464(monotherapy)

Pierre Fabre Medicament

Phase 2D3 antagonist, 5-HT1A partial

agonist

Superior vs placebo: PANSS total, positive and general subscale scores

Not superior: PANSS negative and CGI-S

Lumateperone (ITI-007)(monotherapy)

Intra-Cellular Therapies

Phase 3, under FDA

review

5-HT2A antagonist5-HT transport inhibitor

Presynaptic D2 partial agonist / Postsynaptic D2 antagonist

D1-regulated NMDA and AMPA agonist

42 mg superior vs placebo (2 of RCTs): PANSS total and PANSS positive subscale

scores, CGI-SNot superior: PANSS negative and

general subscale scores

Agents in Development for Total Symptoms of Schizophrenia (cont’d)

BNSS = Brief Negative Symptom Scale; PDE = phosphodiesterase; MADRS = Montgomery–Åsberg Depression Rating Scale; N/A = not applicable; TAAR = trace-amine associated receptor.Adapted from: Krogmann A, et al. CNS Spectrums. 2019;24(Suppl 1):38-69.

Treatment Company PhaseMechanism of

ActionResults

MK-8189(monotherapy)

Merck Phase 2 PDE10A inhibitorNegative study: MK-8189 did not separate from

placebo on PANSS total, but risperidone did

RO5263397(monotherapy)

Roche Phase 3 TAAR1 agonist Not available

SEP-363856(monotherapy)

Sunovion Phase 3 TAAR1 agonistSuperior vs placebo: PANSS total and all 3 subscale scores, CGI-S, BNSS, and MADRS

Sodium Nitroprusside(monotherapy)

N/A N/A Nitric oxide donorFirst trial: Positive

3 subsequent trials: Negative

TAK-063(monotherapy)

Takeda Phase 2 PDE10A inhibitorNegative study: TAK-063 failed to separate

from placebo on the primary endpoint (PANSS total, effect size = 0.31)

Agents in Development for Negative Symptoms and Cognitive Dysfunction in Schizophrenia

DAAO = D-amino acid oxidase; GLYT-1 = glycine transporter 1.Adapted from: Krogmann A, et al. CNS Spectrums. 2019;24(Suppl 1):38-69.

Treatment Company Phase Mechanism of Action ResultsTarget: Negative Symptoms

LuAF-11167(monotherapy)

Lundbeck Phase 2 PDE10 inhibitor Not available

Pimavanserin(add-on)

Acadia Phase 2 5-HT2A inverse agonist Not available

Roluperidone (MIN-101)(monotherapy) Minerva Phase 3

5-HT2A antagonistSigma 2 antagonist

Alpha1-adrenergic antagonist

Superior vs placebo: PANSS negative factor score (pentagonal model), PANSS

negative, total and activation factor scores, CGI-S, and BNSS). No difference

in PANSS positive score, depression

TAK-831(monotherapy)

Takeda Phase 2 DAAO inhibitor Not available

Target: Cognitive Dysfunction BI-425809(add-on)

Boehringer Ingelheim

Phase 2 GLYT-1 inhibitor Not available

Cannabidiol(add-on)

N/A N/APartial cannabinoid1 receptor antagonist, calcium channel

modulator 2 negative studies

Agents in Development for Resistant / Residual Positive Symptoms of Schizophrenia

QOLS = Quality of Life Scale; SANS = Scale for the Assessment of Negative Symptoms.Adapted from: Krogmann A, et al. CNS Spectrums. 2019;24(Suppl 1):38-69.

Treatment Company Phase Mechanism of Action Results

LuAF-35700 Lundbeck Phase 3D1 > D2 antagonist5-HT2A antagonist5-HT6 occupancy

Negative study: LuAF-35700 was not superior to, but as effective as risperidone and olanzapine

Pimavanserin Acadia Phase 3 5-HT2A inverse agonist

Negative study: PANSS total score (trend) in entire population,

BUT positive study for PANSS total and CGI-S in preplanned EU subgroup (80%) analysisAlso, significant superiority for negative

symptoms in the entire sample

Sodium Benzoate N/A N/A DAAO inhibitor2 positive studies: Superior vs placebo on

PANSS total and PANSS subscales, SANS, GAF (1 study), QOLS, CGI, depression (1 study)

Agents in Development / Recently Approved for Amelioration of Nonadherence in Schizophrenia

Brand names are included in this table for participant clarification purposes only. No product promotion should be inferred.ISM = in situ microparticle.Adapted from: Krogmann A, et al. CNS Spectrums. 2019;24(Suppl 1):38-69.

Treatment Company Phase Mechanism of Action Results

Aripiprazole LauroxilNanoCrystal® Dispersion (NCD; Aristada Initio®)

Alkermes FDA-approvedPartial D2 agonist

Partial 5-HT1A agonist5-HT2A antagonist

The 1-day regime groups had comparable aripiprazole exposure to the corresponding 21-day group

Risperidone ISM® (Doria®)LaboratoriosFarmacéu-ticos Rovi

Phase 35-HT2A antagonist

D2 antagonist

Superiority vs placebo: PANSS total and CGI-S scores

(12-week study)Risperidone once-monthly IM (TV-46000)

Teva Phase 35-HT2A antagonist

D2 antagonistNot available

Paliperidone Palmitate 6-monthly formulation

Janssen Phase 35-HT2A antagonist

D2 antagonistNot available

Risperidone subcutaneous (Perseris™) Indivior

FDA-approved5-HT2A antagonist

D2 antagonist

Superiority vs placebo: PANSS total, positive and general

subscale scores, CGI-S (8-week study)

Not superior: PANSS negative subscale score

Agents in Development / Recently Approved for Amelioration of Adverse Effects in Schizophrenia

AIMS = Abnormal Involuntary Movement Scale; CGI-TD = Clinical Global Impression-Tardive Dyskinesia Scale; TD = tardive dyskinesia; VMAT-2 = vesicular monoamine transporter 2.Krogmann A, et al. CNS Spectrums. 2019;24(Suppl 1):38-69. Solmi M, et al. Drug Des Devel Ther. 2018;12:1215-1238.

Treatment Company PhaseMechanism of

ActionResults

Samidorphan + Olanzapine (ALKS 3831)

AlkermesPhase 3,

under FDA review

µ-opioid antagonist + olanzapine

Superior vs olanzapine + PBO:Percent weight gain, ≥ 10% weight gain,

≥ 7% weight gainSimilar superiority as olanzapine vs placebo for acute exacerbation as

olanzapine + placebo (4-week study)

Deutetrabenazine Teva FDA-approved VMAT-2 antagonistSuperior vs placebo:

AIMS total score, TD response, CGI-TD

Valbenazine Neurocrine FDA-approved VMAT-2 antagonistSuperior vs placebo:

AIMS total score, TD response

What about Adherence?

Roger was put on haloperidol decanoate because he was not consistent with taking his oral medications

After his last hospitalization he agreed to taking his medication by injection so that he would not be “nagged”

every day at his supervised residence

Stopping Medication is the Most Powerful Predictor of First-Episode Relapse

• Relapse risk is 5× higher after a first-episode patient stops antipsychotic medication

• Predictors of nonadherence in first year– Early adolescent premorbid

adjustment (P<.01)– Worse premorbid cognitive

function (P=.01)– Parkinsonian side effects (P=.01)– Worse executive function (P=.02)

Robinson D, et al. Arch Gen Psychiatry. 1999;56(3):241-247. Robinson DG, et al. Schizophr Res. 2002;57(2-3):209-219.

Sample of 104 patients with first-episode schizophrenia who responded to treatment of their

index episode, but were at risk for relapse.

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Consistent Medication Treatment is Key in Preventing Relapse

• Within 2 years about 75% relapse when off medications vs 25% when on medications – medications are not perfect, but much better than not taking them

• With drug discontinuation, there is no reliable indicator to differentiate the minority who will not relapse from the majority who will relapse

• Risk of relapse is 3× as high (75/25 = 3) when not taking medication

• Number needed to treat (NNT) is 2 (1/[.75-.25] = 2)• For every 2 persons taking medication vs not taking

medication you avoid 1 relapse event over a 2-year periodBlackwell B. Clin Pharmacol Ther. 1972;13(6):841-848. Hirsch SR, et al (Eds). Schizophrenia. Oxford, England: Blackwell Science; 1995:443-468. APA Work Group on Schizophrenia. Practice Guideline for the Treatment of Patients With Schizophrenia. Second Edition. 2010. https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/schizophrenia.pdf. Accessed February 22, 2019. Citrome L. Acta Psychiatr Scand. 2010;121(2):94-102.

Urgent! Suicide Attempts Increase When Therapy is Interrupted

Herings RM, et al. Pharmacoepidemiol Drug Saf. 2003;12(5):423-424.

Data obtained from drug-dispensing and hospital discharge records (Netherlands) for patients with schizophrenia (sample size, 603) in database (N=865,000) with drug interruption and ≥ 30-day gap in treatment. Risk estimates were controlled for differences in age and gender.

Age/gender-adjusted relative risk increased 4.2×(95% CI:1.7–10.1)

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2020

72

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60

When Treatments Fail

• Wrong diagnosis and thus incorrect treatment• Wrong dose of the right medication• Inadequate duration of treatment• “Treatment resistance”• Think about nonadherence

Nosé M, et al. Psychol Med. 2003;33(7):1149-1160. Weiden P, et al. Psychiatr Serv. 1995;46(10):1049-1054.

When Treatments Fail

• Wrong diagnosis and thus incorrect treatment• Wrong dose of the right medication• Inadequate duration of treatment• “Treatment resistance”• Think about nonadherence

Medication adherence is poor across most chronic physical and psychiatric disorders

~ 75% of patients with schizophrenia become nonadherent within 2 years of hospital discharge

Nosé M, et al. Psychol Med. 2003;33(7):1149-1160. Weiden P, et al. Psychiatr Serv. 1995;46(10):1049-1054.

Partial Adherence in Schizophrenia Begins Early and Prevalence Increases over Time

Velligan DI, et al. Psychiatr Serv. 2003;54(5):665-667. Weiden PJ, et al. Medication noncompliance in schizophrenia: I. assessment. Journal of Practical Psychiatry and Behavioral Health. 1997;3:106-110.

Time from Discharge

50

75

25

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40

50

60

70

80

10–14 Days 1 Year 2 YearsPa

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Pa

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Unfortunately, We Overestimate Adherence

• Nonadherence viewed as failure → consistent bias to overestimate adherence/underestimate nonadherence

• We assume lack of adequate response as “treatment-resistance” and lack of efficacy for the antipsychotic for that patient– This is a possible explanation for high dosing of antipsychotics,

polypharmacy with other antipsychotics, and combination treatment with anticonvulsants

• This is a no-win cycle: adherence is even more of a challenge with complex regimens

Velligan DI, et al. Psychiatr Serv. 2007;58(9):1187-1192.

• Poor adherence to antipsychotic medication is common and likely exists in your practice

• Poor adherence will drive poor outcomes

Risk Factors for Nonadherence (but differs for each patient and can change over time)

Velligan DI, et al. J Clin Psychiatry. 2009;70 Suppl 4:1-46. Lee S, et al. Soc Sci Med. 2006;62(7):1685-1696.

Patient-related• Poor insight• Negative attitude

toward medication • Prior nonadherence • Substance abuse• Cognitive impairment

Treatment-related• Side effects• Lack of efficacy/

continued symptoms

Environment/Relationship-related• Lack of family/social support• Problems with therapeutic

alliance• Practical problems

(financial, transportation, etc.)

Societal-related• Stigma attached to illness• Stigma caused by medication

side effects

Medication-Related Side Effects and Nonadherence

• Potential drivers– Level of distress rather than

severity (as perceived by the patient and not by the clinician; eg, what is “mild” or “severe” is in the eye of the beholder)

– Attribution to the medication (eg, “my teeth itch” can drive poor adherence)

– Varies from patient to patient

• Most commonly associated with nonadherence– Weight gain (patient attitudes

vary and may be offset by efficacy after many failures)

– Sedation– Akathisia– Sexual dysfunction– Parkinsonian symptoms– Cognitive problems

• Influencing clinician response to a side effect is objective severity and ultimately safety and risk

Velligan DI, et al. J Clin Psychiatry. 2009;70 Suppl 4:1-46. Weiden PJ, et al. J Clin Psychiatry. 2007;68 Suppl 6:14-23.

What’s the next step?

• If the adherence problem is that the patient will not, focus intervention on strengthening perceived benefits of medication and minimizing perceived costs/harms – use Motivational Interviewing

• If the adherence problem is that the patient cannot, then address barriers to adherence – Pill boxes in obvious locations – Self-monitoring tools– Establishment of routines– Consider LAI medication, but not all antipsychotics are

available in that formulationWeiden PJ. J Clin Psychiatry. 2007;68 Suppl 14:14-19.

Effective Communication Strategies

Do our preconceived notions influence what we offer to patients? Let’s use LAI antipsychotics as an example.

How can we best engage Roger in participating in his treatment decision-making?

Psychiatrists Cite Multiple Reasons for Not Prescribing LAI Atypical Antipsychotics

Heres S, et al. J Clin Psychiatry. 2006;67(12):1948-1953.

SufficientAdherence

to Oral Drug

PatientRefusal

Antipsychotic Not Available

as LAI

Costs of Drug

Not Appropriate Option after

Relapse

Poorer Control of Effect

Compared to Oral Drug

0

10

20

30

40

50

60

70

80

90

100

Psy

chia

tris

ts (

%)

86%80%

75%71%

68%

58%

High EPS Risk with LAI

31%

Estimated and actual fears as well as experienced factors affecting the decision to decline LAI

0

20

40

60

80

100

Pain Tied toclinic

Observationtime

Embarrasing Reduction inautonomy

Cannotdecide whento take themedicine

Feelingof being

controlled

Stigmatizing

Healthcare staff(estimation)

Patients on per oraltreatment(actual fears)

Patients on LAI(experiences)

Decisive todecline LAI

Does notaffect at all

** * *** *** ** ** * ***

†

Large impact tosay NO to LAT

Noimpact Pain Bound to

the clinic

ObservationTime with OLA-LAT

Embarass-ment

Less self

dependent

Can’t decide yourself

when drugis taken

Feeling of being

controlled

Stigma

Doctors’ or nurses’beliefs(n=63)

Patients’ concern(patient on tablet)(n=101)

Patients’experience(patient on LAT)(n=63)

Overestimation of Reasons for Rejection of LAIs by Doctors or Nurses vs LAT-inexperienced Patients vs LAT-experienced Patients Except for Observation Time with OLA-LAT

Cahling L, et al. BJPsych Bull. 2017;41(5):254-259.

Patients are Willing to Accept LAI Antipsychotic Therapy When Properly Informed

• In a survey of psychiatrists– Patient refusal was cited as a primary reason for not prescribing LAI

antipsychotics• In a survey of patients without LAI antipsychotic experience

– 79% cited having never been informed about the option by their psychiatrist

– 75% of psychiatrists felt that they informed the patient, but only 33% of patients felt informed

• In a survey of patients with > 3 months of LAI antipsychotic experience– Injectable antipsychotics were the preferred formulation– 70% of patients felt better supported in their illness by virtue of regular

contact with the doctor or nurse who administered their injectionHeres S, et al. J Clin Psychiatry. 2006;67(12):1948-1953. Jaeger M, et al. Psychiatry Res. 2010;175(1-2):58-62. Caroli F, et al. Patient Prefer Adherence. 2011;5:165-171.

Communication Style: Motivational Interviewing

• Basic premise of MOTIVATIONAL INTERVIEWING: A patient’s ambivalence to change is normal and that all patients vary in their readiness to change

• Use open-ended questions and reflective listening• Remember RULE

– Resist making too many suggestions– Understand the patient’s motivation– Listen with a patient-centered empathic approach– Empower the patient

Haque SF, et al. Motivational interviewing: The RULES, PACE, and OARS. Current Psychiatry. 2019;18(1):27-28. Lewis-Fernández R, et al. J Clin Psychiatry. 2018;79(3).

Motivational Interviewing: Basic Principles

• Autonomy Patient has the right to self-directionCaregiver affirms this, but also provides input

• Collaboration Patient is their own expertCaregiver builds partnership

• Evocation Patient has the resources to changeCaregiver elicits the change

Modified based on material from: Maria Arpa. Centre for Peaceful Solutions. www.centreforpeacefulsolutions.org/.

Motivational Interviewing: Skills and Process

• To practice Motivational Interviewing we must– Connect with our patients– Listen actively– Understand patients’ values, fears, qualities, and skills– Be nonjudgmental, collaborative, challenging, genuine, flexible,

empathic, and respectful– Identify and work with stages of change

Modified based on material from: Maria Arpa. Centre for Peaceful Solutions. www.centreforpeacefulsolutions.org/.

Motivational Interviewing: Stages of Change

Modified based on material from: Maria Arpa. Centre for Peaceful Solutions. www.centreforpeacefulsolutions.org/.

State Explanation Facilitator Role Outcome

1. Pre-awarenessPatient is not aware or in denial of any problem or risk to well-being

Consciousness raising of reality vs perception

Raise doubt in patient about behavior

2. ConsiderationEvoking reasons for change in behavior

Facilitate understanding of risk of not changing

Reasons for self-efficacy are clear

3. PreparingWorking with the emotional ambivalence

Understand the consequences of change

Development of a workable strategy

4. Action Implementing the strategyHelp with implementation and problem-solving

Patient takes an action which changes behavior

5. MaintenanceIdentifying what works and continuing

Reviewing actions and refining strategy

Continuation towards change

6. RelapsePatient becomes stuck and reverts to old behavior

Re-motivate patient by celebrating the actions and mourning the relapse

Implements strategy and takes actions to support change

Bottom Line: Communication Matters

• A study of communication patterns in the offer of LAI antipsychotics made by psychiatrists to patients with schizophrenia at 10 community mental health clinics found that– Only 9% of the communication of psychiatrists presenting LAI

antipsychotics to patients focused on positive aspects– Consequently, only 11 of 33 LAI treatment recommendations

(33%) were accepted by patients– During a post-visit interview, in which LAI antipsychotics were

presented in a more positive light and with more information, 27 of 28 patients (96%) who seemed to decline the initial recommendation changed their mind, stating that they would be willing to try LAI treatment

Weiden PJ, et al. J Clin Psychiatry. 2015;76(6):684-690.

The Evidence-Based Practice of Medicine

How do we put it all together?

Roger is essential to this process!

ClinicalJudgment

RelevantScientificEvidence

EBM

Patients’ Values and Preferences

What is Evidence-Based Medicine?

Sackett DL, et al. BMJ. 1996;312(7023):71-72. Citrome L, et al. Int J Clin Pract. 2019;73:e13351.

ClinicalJudgment

RelevantScientificEvidence

EBM

Patients’ Values and Preferences

What is Evidence-Based Medicine?

Sackett DL, et al. BMJ. 1996;312(7023):71-72. Citrome L, et al. Int J Clin Pract. 2019;73:e13351.

Roger

YouThe Evidence and not the Eminence

Evidence Changes over Time!Getting “Out-of-Date” Can Result in:

• Under-use of effective interventions

• Over-use of unproven interventions

• Unnecessary variations in practice

• Eminence-based vs evidence-based practice

• Reliance on LPIT (Last Patient I Treated)

The Philosophy of EBM to the Rescue!

“Evidence based medicine is the conscientious, explicit, and judicious use of current best evidence in making decision

about the care of individual patients.”

“…the integration of best research evidence with clinical expertise and patient values.”

Sackett DL, et al. BMJ. 1996;312(7023):71-72.

Concepts Related to Benefit / Risk:Effect Size – NNT (or NNH)

• NNT is one measure of effect size• It is independent of P-value and does not say anything about the

likelihood of the difference between treatments being due to chance alone

• Helps you judge the clinical significance of a statistically significant result

NNH = number needed to harm; NNT = number needed to treat.Citrome L. Acta Psychiatr Scand. 2010;121(2):94-102.

NNT for Benefits, NNH for Harms

• How many patients would you need to treat with Drug A instead of Drug B before you would encounter 1 extra outcome of interest, such as response (NNT) or an adverse event (NNH)

Citrome L. Acta Psychiatr Scand. 2010;121(2):94-102.

Small NNT Numbers = Bigger Difference between Drug A and Drug B

Calculating NNT is Easy

Citrome L. Acta Psychiatr Scand. 2010;121(2):94-102.

What is the NNT for an outcome for Drug A vs Drug B?

fA = frequency of outcome for Drug AfB = frequency of outcome for Drug B

Attributable Risk (AR) = fA – fBNNT= 1/AR

By convention, when not presenting fractions, we round up the NNT to the next higher whole number

For example, Drug A results in remission 50% of the time, but Drug B results in remission 20% of the time.

NNT = 1/[0.50-0.20] = 1/0.30 = 3.33 Round up to 4

What is a Clinically Important NNT or NNH?

• A large NNT of 100 or more means that there is little difference between choosing Drug A or Drug B for the outcome measured

• A small NNT of 2 would be a hugely important difference

• NNT values < 10 denote a potentially useful intervention

• NNH values > 10 denote a potentially tolerable intervention

• Some NNTs may be clinically important, even if they are relatively large, for example when the outcome is death

Citrome L. Acta Psychiatr Scand. 2008;117(6):412-419.

Efficacy of Antipsychotics

• Clinical trials compare drugs with placebo

• We can indirectly compare drugs to see how they do vs placebo

• In general for the outcome of at least 20% or 30% improvement on the PANSS, NNT < 10 for acute studies for antipsychotic vs placebo

• In general for the outcome of avoidance of relapse, NNT < 10 for maintenance studies for antipsychotic vs placebo

“Your individual mileage may vary”

Citrome L. CNS Drugs. 2013;27(11):879-911. Citrome L. Expert Rev Neurother. 2017;17(10):1029-1043.

Tolerability of Antipsychotics

“All over the map”

and

“It depends on the patient”

Citrome L. CNS Drugs. 2013;27(11):879-911. Citrome L. Expert Rev Neurother. 2017;17(10):1029-1043.

ClinicalJudgment

RelevantScientificEvidence

EBM

Patients’ Values and Preferences

What is Evidence-Based Medicine?

Sackett DL, et al. BMJ. 1996;312(7023):71-72. Citrome L, et al. Int J Clin Pract. 2019;73:e13351.

Need to Match the Right Drug with the Right Patient

• Heterogeneity of antipsychotics + heterogeneity of patients = opportunity for innovative decision-making

• Perfection is not possible• Is efficacy “good enough”?• Is tolerability “good enough”?• Is adherence “good enough”?

Reverberations from Side Effects How Patient and Clinician Responses May Differ

Weiden PJ, et al. J Clin Psychiatry. 2007;68 Suppl 6:14-23.

Side EffectAppears

Subjective Distress

Objective Severity

Adherence Impact

Safety and Risk

AntipsychoticNNH for

Weight Gain ≥ 7% NNH for Somnolence

Adverse EventsNNH for Akathisia Adverse Events

Aripiprazole 21 20 a 25Brexpiprazole 17 50 b 112 Cariprazine (to 6 mg/day) 34 100 b 15Lurasidone 67 11 10Olanzapine 6 a 7 a 25Paliperidone 35 42 39Quetiapine Extended-Release 22 7 188Quetiapine Immediate-Release 6 10 a NARisperidone (to 8 mg/day) 18 a 13 15Ziprasidone 16 15 100

NNH vs Placebo for First-Line Oral SGAs in Adults with Schizophrenia Weight Gain, Somnolence, and Akathisia in Acute Short-Term Studies as

Calculated from Product Labeling

aReported in product labeling for schizophrenia and bipolar mania pooled together. bSomnolence, sedation, hypersomnia. NA = no difference or rate with medication is lower than rate with placebo; SGA = second-generation antipsychotic.Citrome L. Neuropsychiatr Dis Treat. 2018;14:2563-2577. Citrome L. Clin Schizophr Relat Psychoses. 2016;10(2):109-119.

AntipsychoticNNH for

Weight Gain ≥ 7% NNH for Somnolence

Adverse EventsNNH for Akathisia Adverse Events

Aripiprazole 21 20 a 25Brexpiprazole 17 50 b 112 Cariprazine (to 6 mg/day) 34 100 b 15Lurasidone 67 11 10Olanzapine 6 a 7 a 25Paliperidone 35 42 39Quetiapine Extended-Release 22 7 188Quetiapine Immediate-Release 6 10 a NARisperidone (to 8 mg/day) 18 a 13 15Ziprasidone 16 15 100

NNH vs Placebo for First-Line Oral SGAs in Adults with Schizophrenia Weight Gain, Somnolence, and Akathisia in Acute Short-Term Studies as

Calculated from Product Labeling

Citrome L. Neuropsychiatr Dis Treat. 2018;14:2563-2577. Citrome L. Clin Schizophr Relat Psychoses. 2016;10(2):109-119.

NNH values < 10 mean you will encounter these AEs as often as efficacy!

Treatment is a Dynamic Process

• Switches offer both opportunity and risk• A medication does not have to be perfect

• Does it relieve symptoms well enough?• Is it tolerated well enough?• Is the patient willing to take it?

• Shared decision-making: Getting the patient to “buy-in” is key in promoting adherence

• Individuals have their own preferences and values regarding which symptoms are important to them

• Individuals have their own preferences and values regarding which tolerability issues are important to them

Don’t Forget about the Whole Team

• Addressing substance use

• Intensive case management

• Assertive community treatment

• Vocational rehabilitation

• Cognitive remediation

Choosing an Antipsychotic: Switch or Stay?

• Past history of efficacy of drug response

• Nature of psychiatric condition, acuity

• Target signs and symptoms

• Patient preference, history of adherence

• Need for special monitoring

• Amenable to other interventions to address tolerability?– Diet, exercise, and statins or other adjunctive medicines for

obesity and dyslipidemia– β-blockers for akathisia– Anticholinergic medications or amantadine for EPS

Conclusions

• Antipsychotics vary more regarding side effects than for efficacy• On the horizon are antipsychotics that may be better tolerated, as

well as medications that may be helpful for negative symptoms and cognitive impairment

• Adherence remains problematic for many people• Engaging patients in their treatment requires care in how we

communicate• Assessing new medications will require some basic skills in

interpreting effect sizes; NNT and NNH are useful ways at looking at this

Q&A