Long-Acting Injectable Antipsychotics: Where Do They Fit in the - - PowerPoint PPT Presentation

Long-Acting Injectable Antipsychotics: Where Do They Fit in the Treatment Plan?

Christoph U. Correll, MD John Lauriello, MD

Objectives

• Monitor adherence to antipsychotic treatment
• Identify patients who may benefit from

long-acting injectable, or LAI, antipsychotic treatment and present them with objective information on the risks and benefits

• And, use LAI antipsychotics safely and effectively in

patients with schizophrenia and related disorders

• 33-year-old construction worker
• Diagnosed with schizophrenia

at age 30

• Treated with a second-generation

antipsychotic (SGA), with good effect

• “Was doing so well” he decided to

stop the medication

• Hospitalized for 2 weeks
• Lost his job and had to move

in with his parents

Felix

Multiple relapses and subsequent exacerbations can cause:

• Increased burden on family and caregivers
• Greater use of healthcare resources
• Increased risk of suicide attempts
• Long-term symptoms and disability
• Decrease in treatment response
• Progressive decline in brain function

Higashi et al. Ther Adv Psychopharmacol. 2013;3(4):200–218. Emsley et al. BMC Psychiatry 2013;13:50.

Importance of Relapse Prevention

• Earlier onset of illness
• Substance use disorder
• Social functioning at baseline
• More severe symptoms
• Antipsychotic medication nonadherence

(hazard ratio for an initial relapse, 4.89)

Predictors of Relapse

Robinson et al. Arch Gen Psychiatry. 1999;56:241–247. Ascher-Svanum et al. BMC Psychiatry. 2010;10:2.

Study population included patients with recent onset of schizophrenia, schizophreniform, or schizoaffective disorders

10 20 30 40 50 60 70 80 Poor Good Relapse Rate (%) 69% 18% Adherence With Oral or Depot Antipsychotics (N=50)

Link Between Adherence and Relapse

Morken et al. BMC Psychiatry. 2008;8:32.

Illness severity Frequency of treatment (how often is medication taken) Relationship with family Side effects Relationship with physician Cost of treatment Treatment setting (inpatient/outpatient) Attitudes toward treatment (physician/patient)

Kane et al. World Psychiatry. 2013;12(3):216–226.

Factors Influencing Treatment Adherence

• Patient/family report
• Self-assessment questionnaires
• Diaries

Patient-Related Physician-Observed

• Serum drug levels (blood draws/hair analysis)
• Adverse events
• Biomarkers

Physiologic

• Electronic pill trays
• Medication event monitoring system cap
• Medication event marker

Electronic

Kane et al. World Psychiatry. 2013;12(3):216–226.

Methods for Monitoring Medication Adherence

• Pill count
• Prescription refills
• Clinical response
• If injectable agent,

missed shot

Novak-Grubic & Tavcar. Eur Psychiatry. 2002;17(3):148–154.

70% of patients who discontinued antipsychotics relapsed within the first year

N=56 30 patients discontinued treatment (54%) 26 patients continued treatment (46%)

9 patients who discontinued treatment did not relapse (30%) 21 patients who discontinued treatment relapsed (70%)

First-Year Outcomes After Discharge

• 55-year-old woman with

schizophrenia (since age 25)

• Tried multiple first-generation

antipsychotics (FGAs) when first diagnosed

• Always stopped them secondary

to EPS

• Finally, she was convinced to try

an SGA, with no EPS noted

• But, at her 3-month follow-up,

she had stopped the SGA

Rachel

20 40 60 80 100 Haloperidol Perphenazine

Typical Antipsychotics

20 40 60 80 100 Risperidone Olanzapine Quetiapine

Atypical Antipsychotics

12-Month Adherent Fill Rate (%) Dolder et al. Am J Psychiatry. 2002;159(1):103–108.

Oral Atypical Medications Have Not Solved the Issue of Nonadherence

Relapse

• Number needed to treat (NNT) for relapse prevention= 3
• 27% relapse with antipsychotic drugs vs 64% with placebo

Readmission

• NNT= 5
• 10% readmission with antipsychotics vs 26% with placebo

Employment rate did not differ between antipsychotic and placebo groups

Leucht et al. Lancet. 2012;379(9831):2063–2071.

Antipsychotic Drugs Versus Placebo

Meta-analysis of randomized controlled trials (RCTs) with FGAs and SGAs in stabilized patients with schizophrenia, 1950–2014 Risk of relapse: Compared with continuous treatment, 3 times greater with intermittent treatment and 6 times greater with placebo

De Hert et al. CNS Drugs. 2015;29(8):637–658.

Continuous Versus Intermittent Antipsychotic Treatment

Perceived Advantages Perceived Disadvantages No need for daily medication Reluctance to get shots Ease of compliance monitoring Potential for injection-site complications Stable plasma levels No rapid dose adjustments Reduced risk for relapse/rehospitalization Different side effects (eg, anxiety, akinesia, cholesterol) Fewer dose-related side effects (eg, extrapyramidal)

Pros and Cons of LAIs

Fleischhacker et al. Managing Schizophrenia: The Compliance Challenge. 2nd ed.; 2007. Misawa et al. Schizophr Res. 2016 Oct;176(2–3):220–30.

Antipsychotic Base Dose Interval Oral Supplementation Needed Time to Peak Postinjection Observation

Fluphenazine decanoate Oil Varies No 2–4 days No Haloperidol decanoate Oil 4 weeks No 6–7 days No Risperidone microspheres Water 2 weeks 3 weeks 4–6 weeks No Olanzapine pamoate Water 2 or 4 weeks No 4 days At least 3 hours Paliperidone palmitate Water Monthly No 13 days No Paliperidone palmitate (ER) Water Every 3 months No 30–33 days No Aripiprazole monohydrate Water Monthly 2 weeks 5–7 days No Aripiprazole lauroxil (ER) Water Monthly or every 6 or 8 weeks 3 weeks 4 days No

FGAs

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

Characteristics of FGA and SGA LAIs

SGAs

Response:

• NNT=4 for SGA LAIs vs placebo
• No difference for SGA LAIs vs oral antipsychotics

Fusar-Poli et al. Int Clin Psychopharmacol. 2013;28(2):57–66

Efficacy of LAIs

Antipsychotic EPS Weight Gain QTc Prolongation Sedation Prolactin Elevation Haloperidol

Marked Mild Mild Moderate Moderate

Risperidone

Moderate Moderate Moderate Moderate Marked

Paliperidone

Moderate Moderate Mild Mild Marked

Olanzapine

No effect Marked Mild/Moderate Moderate/ Marked Mild

Aripiprazole

Mild Mild No effect/Mild Mild No effect

Leucht et al. Lancet. 2013;382(9896):951–962.

Adverse Effect Differential

• Study included 16 RCTs
• 119 adverse effects were studied
• 115 adverse effects did not differ significantly between

LAIs and oral antipsychotics

• LAIs were associated with significantly more anxiety,

akinesia, and low-density lipoprotein cholesterol change, but also with significantly lower prolactin change

Misawa et al. Schizophr Res. 2016 Oct;176(2-3):220–230.

Adverse Effects With LAI vs Same Oral Antipsychotics

• N=305; schizophrenia or schizoaffective disorder
• LAI risperidone vs oral SGA of clinician’s choice
• 30 months
• No significant treatment difference in time to relapse or

hospitalization

• Limitations: no focus on previously nonadherent

patients, biweekly monitoring, greater flexibility in oral treatment

Buckley et al. Schizophr Bull. 2015;41(2):449–459.

PROACTIVE Study

Hospitalization Risk Number of Hospitalizations Kishimoto et al. J Clin Psychiatry. 2013;74(10):957-965.

Meta-analysis of 25 mirror-image studies showed that LAIs were associated with less hospitalization than oral agents

Risk Ratio 0.430 Lower Limit 0.350 Upper Limit 0.527 Z Value

• 8.074

P Value .0000 Rate Ratio 0.381 Lower Limit 0.283 Upper Limit 0.512 Z value

• 6.397

P Value .0000

LAI vs Oral Antipsychotics

• Patients with schizophrenia who had poor antipsychotic

response were randomly assigned to treatment switches and followed for 1 year

• 43% of patients were taking LAIs before randomization

(n=155)

• For patients with inconsistent adherence, switching from

LAI to oral antipsychotic was associated with poorer

• utcomes (symptoms, functioning, quality of life) than

switching from one oral agent to another

• For patients who were consistently adherent, no significant

change was noted between LAI-to-oral and oral-to-oral switches

Barnes et al. Br J Psychiatry. 2013;203(3):215–220.

CUtLASS Study

• Patients who switched from risperidone LAI to

paliperidone LAI had fewer relapse-related events (eg, hospital visits) than patients who switched to an oral antipsychotic (26 vs 32)

• Patients also had a longer time to an event when

switched to the paliperidone LAI (70 vs 47 days)

Voss et al. Int Clin Psychopharmacol. 2015; 30(3): 151–157.

Switching from LAI to LAI or Oral Antipsychotic

• 21-year-old college student
• Joined a fraternity, began smoking

marijuana

• Brought to emergency department

by campus police for behaving strangely (second time this semester)

• Had been prescribed an

antipsychotic the first time, but did not take it once released from the hospital

Josh

Carbon & Correll. Dialogues Clin Neurosci. 2014;16(4):505–524. Fixed Risk Factors Modifiable/Preventable Risk Factors Male sex Longer duration of untreated psychosis Earlier illness onset Greater number of relapses Premorbid developmental delay Comorbidities (eg, substance use) Longer illness duration Early nonresponse to antipsychotic medication Greater severity of illness Nonadherence

Clinical Predictors of Poor Outcomes

• 2,588 consecutive patients with a first hospitalization for

schizophrenia were studied

• 1,507 (58%) of patients picked up their antipsychotic

treatment during the first 30 days after discharge

• 1,182 (46%) continued treatment for 30 days or longer
• Among patients receiving injectable agents, risk of

rehospitalization was about one-third the risk for those taking oral medications (adjusted hazard ratio=0.36)

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

Oral vs LAI Treatments in First-Episode Patients

5 10 15 20 25 30 35 LAI Risperidone Oral Risperidone

Relapse Rate

Patients with a recent first episode of schizophrenia who received LAI risperidone had significantly fewer psychotic exacerbations &/or relapses than patients who received

• ral risperidone

N=2/40 N=14/43 Subotnik et al. JAMA Psychiatry. 2015 August;72(8):822–829.

Oral vs LAI Risperidone: Relapse

20 40 60 80 100 First relapse Second relapse

Risk of Relapse During 5 Years After Initial Recovery

Risk of relapse increases almost 5 times after discontinuing antipsychotic drug therapy

Robinson et al. Arch Gen Psychiatry. 1999;56(3):241–247.

Predictors of Relapse Following First Episode

Subotnik et al. JAMA Psychiatry. 2015; 72(8):822–829. 20 40 60 80 100 LAI Risperidone Oral Risperidone

Adherence Rates During Follow Up (12 Months After First Episode)

Patients With “Excellent” Adherence (%)

Oral vs LAI Risperidone: Adherence

100 200 300 400 500 LAI Paliperidone Oral Antipsychotics Days 10 20 30 Oral Antipsychotics LAI Paliperidone Measured in %

29% relative risk reduction

Schreiner et al. Schizophr Res. 2015;169(1–3):393–399.

Time Until 15% of Patients Relapsed Patients Meeting Relapse Criteria Over 24 Months

Patients were diagnosed with schizophrenia 1 to 5 years before the trial.

Relapse With Paliperidone Palmitate vs Oral Antipsychotics

Alphs et al. J Clin Psychiatry. 2015;76(5):554–561.

PRIDE study examined time to first treatment failure (eg, arrest, hospitalization, treatment change or discontinuation, increased service use). During 15 months, first treatment failure occurred in 40% of those taking paliperidone palmitate vs 54% of those taking oral antipsychotics.

Paliperidone LAI vs Oral Antipsychotics in Patients With History of Incarceration

• In 15-month PRIDE study, 60% of patients had substance

abuse

• In substance abuse cohort:

Treatment failure occurred among 56% of those taking paliperidone palmitate and 64% of those taking oral antipsychotics

• In those without substance abuse:

Treatment failure occurred among 37% of those taking paliperidone palmitate and 54% of those taking oral antipsychotics

Lynn Starr et al. Schizophr Res. 2017. pii: S0920-9964(17)30264–30265.

Paliperidone LAI vs Oral Antipsychotics in Patients With History of Incarceration and Substance Abuse

Heres et al. J Clin Psychiatry. 2006;67(12):1948–1953. EPS = extrapyramidal symptoms

Physician Reasons for Not Prescribing LAI Antipsychotics

10 20 30 40 50 60 70 80 90 100 I knew about the possibility to receive antipsychotics as an injection My psychiatrist informed me about the option of LAI treatment I feel sufficiently informed about different formulations of antipsychotics Patients With LAI Experience Patients Without LAI Experience Although 75% of psychiatrists said they informed their patients about injectable agents,

• nly 21% of patients

not taking LAIs said their doctor informed them about LAIs.

Jaeger & Rossler. Psychiatry Res. 2010;175(1-2):58-62. Patients Agreeing (%)

Are Patients Properly Informed?

5 10 15 20 25 30 35 40 45 50

Injections Tablets Drinkable solutions Orally disintegrating tablets Patient did not know

Treatment Forms

Almost half of patients who had tried at least 2 forms of treatment preferred LAI treatment.

Caroli et al. Patient Prefer Adherence. 2011;5:165–171.

Patients had received an average of 3 forms of treatment; all participants were required to have received an injectable drug.

Patient Treatment Preferences

• Psychotherapeutic approach to help patients understand

their motivations and methods of coping

• Attempt to move patients away from

indecision/ambivalence and toward making decisions and accomplishing goals

• Counseling to help patients activate positive behavioral

change

Miller & Rollnick. Motivational Interviewing: Preparing People To Change Addictive

• Behavior. New York: Guilford Press, 1991.

Rüsch & Corrigan. Psychiatr Rehabil J. 2002;26(1):23–32.

What is Motivational Interviewing?

Physicians should practice:

• Discussing medications and treatment options that may

be difficult

• Connecting with and listening actively to patients
• Understanding patients’ values, fears
• Being nonjudgmental, empathetic, and respectful

Motivational Interviewing Skills

• Discover the patient’s goals
• Be knowledgeable and enthusiastic about the treatment
• ptions
• Encourage patient to ask questions and discuss concerns
• Involve family members or support system in decisions
• Consider involving peer counselors with similar

experiences

Communication Strategies For Presenting LAIs as a Treatment Option

• Nonadherence is a modifiable risk factor for relapse in

patients with schizophrenia

• LAIs are an underutilized treatment option
• Physicians should focus on attitudinal (physician and patient),

service, setting, and system barriers to the appropriate use of LAIs

• Using LAIs more frequently (and earlier) can preserve

psychosocial functioning

• Balance the risks and benefits of LAIs for patients (consider

side effects)

• Decide the best way to communicate with the patient and

family

Summary