LAMP

LAIs Available in Canada
First generation • Fluphenazine decanoate
• Flupenthixol decanoate
• Haloperidol decanoate
• Pipotiazine palmitate
• Zuclopenthixol decanoate
Second generation • Paliperidone palmitate
• Risperidone microspheres

Second Generation LAIs Available in Canada
LAI Indication Properties Mechanism
Paliperidone
palmitate
Schizophrenia Prolonged-release
injectable suspension for
intramuscular
administration
Due to its extremely low water
solubility, paliperidone
palmitate slowly dissolves at the
injection site and is enzymatically
hydrolyzed to paliperidone, which is
taken up in the systemic circulation
Risperidone
microspheres
Schizophrenia and
related disorders
Bipolar disorder
Powder for injectable
prolonged-release
suspension for
intramuscular
administration
Combination of the release profile
and dosing regimens (IM injections
every 2 weeks) results in sustained
therapeutic concentrations

LAI Evidence
 Davis et al (1994)
• Meta-analysis suggested significant superiority for LAIs
compared to orals
 Cochrane Reviews (1999 - 2007)
• Earlier reviews showed no convincing difference
 Leucht et al (2011)
• Recent review showed significant advantages for LAIs
Manchanda R, Chue P, Malla A, et al. Long-acting injectable antipsychotics: evidence of effectiveness and use. Can J Psychiatry.
2013;58(5 Suppl 1):5S–13S.

Cochrane Review of LAIs
Critiques/criticisms of the Evidence
 Use of inpatient samples
 Short-term trials (few weeks)
 Inappropriate randomization
Abhijnhan A, Adams CE, David A, Ozbilen M. Depot fluspirilene for schizophrenia. Cochrane Database Syst Rev. 2007;1:CD001718.
Da Silva Freire Coutinho E, Fenton M, Quraishi SN. Zuclopenthixol decanoate for schizophrenia and other serious mental illnesses.
Cochrane Database Syst Rev. 1999;3:CD001164.

Recent Meta-Analysis
Leucht et al. (2011) Kishimoto et al. (2012)
10 RCTs; n = 1700 21 RCTs; n = 5176
> 1 yr; outpatient only > 6 months; inpatient & outpatient
Inclusion Criteria (narrower)
• Schizophrenia or related disorders
• Any diagnostic system, any age, and gender
• Only long-term studies defined as 1 year or longer
• Outpatient studies
• Studies with less than 25% inpatients or with an initial
inpatient phase were eligible
• Excluded trials with inappropriate randomisation processes
Inclusion Criteria (broader)
• ≥17 years old
• Diagnosis of schizophrenia or schizoaffective disorder
• Included studies having other diagnoses, such as
schizophreniform disorder
• Studies with a duration of at least 24 weeks that provided
information about relapse-related information, such as
study-defined relapse or rehospitalization
• Excluded penfluridol, a once-weekly oral antipsychotic,
considering it neither a LAI or oral antipsychotic
Leucht C, Heres S, Kane JM, et al. Oral versus depot antipsychotic drugs for schizophrenia – a critical systematic review
and meta-analysis of randomised long-term trials. Schizophr Res. 2011;127(1-3):83–92.
Kishimoto T, Robenzadeh A, Leucht C, et al. Long-acting injectable vs oral antipsychotics for relapse prevention in
schizophrenia: A meta-analysis of randomized trials. Schizophr Bull. 2013 Jan 2. Epub ahead of print. P 1-22.

Relapse (Primary Outcome)
 Leucht et al (2011)
• 21.6% LAIs vs 33.3% oral AP (P = 0.0009) - Highly significant
 Kishimoto et al (2013)
• 25.8% LAIs vs 31.4% oral AP (P = 0.41) – Not significant
• Results similar when narrower criteria used
• Fluphenazine LAI 30.6% vs 41.9% oral AP (P = 0.02)
• Not significant for other LAIs (haloperidol, olanzapine,
risperidone, zuclopenthixol) compared to oral APs
Leucht C, Heres S, Kane JM, et al. Oral versus depot antipsychotic drugs for schizophrenia – a critical systematic review and meta-analysis of
randomised long-term trials. Schizophr Res. 2011;127(1-3):83–92.
Kishimoto T, Robenzadeh A, Leucht C, et al. Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: A meta-
analysis of randomized trials. Schizophr Bull. 2013 Jan 2. Epub ahead of print. P 1-22.

Secondary Outcomes
 Rehospitalization rates
 Drop out/discontinuation rates
• From all cause
• Adverse events
 Non-adherence
All of the above findings not significant
Leucht C, Heres S, Kane JM, et al. Oral versus depot antipsychotic drugs for schizophrenia – a critical systematic review and meta-analysis of
randomised long-term trials. Schizophr Res. 2011;127(1-3):83–92.
Kishimoto T, Robenzadeh A, Leucht C, et al. Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: A meta-
analysis of randomized trials. Schizophr Bull. 2013 Jan 2. Epub ahead of print. P 1-22.

Adherence, Rehospitalization and LAIs
Register based case linked study in Finland
• 2588 patients with schizophrenia discharged after first
hospitalization 2000-2007
• 1406 (54.3%) either did not collect an AP prescription or
used their medication for less than 30 days
• Risk of rehospitalization for patients on LAIs was about one-
third of those on oral antipsychotics
.
Tiihonen J. et al. A Nationwide Cohort Study of Oral and Depot Antipsychotics After First Hospitalization for Schizophrenia. American
Journal of Psychiatry. 2011;168(6):603

Poor Adherence is Not Reflected in
Clinical Trials
 Patients are:
• Highly selected,
• Motivated, and
• Closely monitored
 Patients participating in RCTs are more likely to be
willing to take treatment and to be cooperative, thereby
obscuring any observable differences

Second Generation LAIs Available in Canada
SG LAIs Availability Initiation
PaliperidonePalmitate(PP)
Kit contains
• 1 Pre-filled syringe
• 2 needles
• 1” 23G or 1.5” 22G (depending on patient weight and
injection site)
• 50, 75, 100 & 150 mg
• Store at room temperature
Day 1: 150 mg by deep IM deltoid injection
Day 8: 100 mg by deep IM deltoid injection
• Absorption better from the deltoid injection especially during
initial doses
• For patients who have never taken oral paliperidone or
oral/injectable risperidone, it is recommended to establish
tolerability with oral paliperidone or oral risperidone prior
to initiating treatment
Oral Supplement Dosing & Adjustments
• Oral supplementation is not required at initiation
(as per PM)
• Clinically some patients (ie. acutely ill, previously on high
dose medication, those showing breakthrough symptoms)
may require oral supplementation at initiation
• Monthly dosing (50-150 mg) IM Gluteal or Deltoid
• First episode patients may require lower doses
• Adjustment of the maintenance dose may be made monthly
• When making dose adjustments, the prolonged-release
characteristics should be considered, as the full effect of
the dose may not be evident for several months
INVEGA SUSTENNA® Product Monograph, Dec 30, 2013.

Second Generation LAIs Available in Canada (cont’d)
SG LAIs Availability Initiation
RisperidoneMicrospheres(RLAI)
Kit contains:
• 1 vial of Risperidone microspheres
• 1 prefilled syringe containing diluent
• 2 needles
• 2” 20G (gluteal)
• 1” 21G (deltoid)
• 12.5, 25, 37.5 & 50 mg
• Keep refrigerated (2-8 degrees Celsius). Bring to room
temperature before injection
• Use within 6 hours of reconstituting the preparation
• Can stay up to 7 days outside of the refrigerator at
temperatures no greater than 25 degrees Celsius
• 25 mg every 2 weeks by deep IM injection; gluteal
or deltoid
Oral Supplement Dosing & Adjustments
• Oral supplementation should be continued for 3 weeks
after the first injection
• Some experts advocate gradual tapering after 3 weeks.
Patients showing breakthrough symptoms may require
longer period of oral supplementation until the effective
dose of LAI has been established
• Dose can be adjusted monthly [dose range: 25, 37.5, 50 mg
(maximum)]
• In clinical practice, doses of 75 mg have been used for
patients who have shown good tolerability but require
higher dose for full clinical response
• Patient should be continued on lowest dose needed
• Upward dose adjustment should not be made more
frequently than every 4 weeks. The clinical effects of this
dose adjustment should not be anticipated earlier than 3
weeks after the 1st injection with the higher dose.
RISPERDAL® CONSTA® Product Monograph, August 13, 2013

Switching to SG LAIs from an Oral
Antipsychotic
Flexible
50 - 150 mg
(deltoid or gluteal)
Patient
on oral
DAY 1 DAY 8
(+/- 2 to 4 days)*
4 WEEKS
LATER
MONTHLY
(+/- 7 days)*
Paliperidone
Palmitate 150 mg (deltoid)
Paliperidone
Palmitate 100 mg (deltoid)
Flexible
50 - 150 mg
*To avoid a missed dose
Paliperidone Palmitate (PP)
Stop Oral
Approximate conversion: Risperidone oral 2-3 mg (25 mg RLAI), Risperidone oral 4-5 mg (37.5mg RLAI), Risperidone oral 6 mg and over (50 mg RLAI)
These ratios are approximate and may not work for some patients.
Patient
on oral
DAY 1 DAY 21 DAY 28
WEEK 4
EVERY 2
WEEKS
Risperidone Microspheres 25 mg
Stop Oral
EVERY 2
WEEKS
Risperidone Microspheres (RLAI)
Risperidone Microspheres 25 mg
DAY 14
(WEEK 2)
Flexible 25-50 mg
Flexible 25-50 mg
Flexible 25-50 mg
INVEGA SUSTENNA® Product Monograph, Dec 30, 2013. RISPERDAL® CONSTA® Product Monograph, Aug 13, 2013

Switching Between LAI’s
 Tolerability should be established with oral paliperidone
or oral risperidone for patients who have never taken
these agents
 When switching patients who are on a stable dose of a
long-acting injectable, initiate paliperidone palmitate
therapy in place of the next scheduled injection then
continue at monthly intervals
 The one-week initiation dosing regimen is not required

Switching Between LAI’s (cont’d)
Approximate dose equivalence between risperidone microspheres
and paliperidone palmitate (as per PM)
Switching early psychosis patients from risperidone microspheres to paliperidone palmitate may require more careful
dose adjustment
Previous Risperidone
Microspheres Dose
Paliperidone Palmitate
Dose
25 mg every 2 weeks 50 mg eq. monthly
37.5 mg every 2 weeks 75 mg eq. monthly
50 mg every 2 weeks 100 mg eq. monthly
For patients on FG LAIs being switched to SG LAIs it is recommended that they have the injection
on the next scheduled injection day and follow the dosing regimen of SG LAI. Dose is dependent on
whether the patient is on low, average or high dose of FG LAI

Patient Acceptance of LAIs
 Important for physicians and patients to;
• Share knowledge about LAIs
• Reflect on their respective bias and attitude about injections
 Collaborative discussions are essential to gaining
acceptance to any treatment plan
 Motivational Interviewing techniques may help to foster
collaborative discussions

Motivational Interviewing: Definition
 Motivational interviewing has been applied to improve
treatment adherence
 Motivational interviewing matches patients’ level of
problem recognition and motivation to change, with
specific strategies and goals.
Kisely S, Ligate L, Roy MA, Lavery T. Applying Motivational Interviewing to the initiation of long-acting injectable atypical
antipsychotics. Australasian Psychiatry. 2012; 20(2); 138-142.

Motivational Interviewing: Principles
 Motivational interviewing has four principles:
1. Expressing empathy through reflective listening;
2. Developing discrepancy by increasing the perceived
discrepancy between the patient’s present behaviour and his or
her core values;
3. Supporting self-efficacy to bolster patients’ confidence in their
ability to achieve their desired change; and
4. Rolling with resistance by avoiding arguments

Motivational Interviewing: Stages of Change
 Change, as conceptualized in motivational interviewing,
has the following five stages:
• Pre-contemplation
• Contemplation
• Preparation
• Action
• Maintenance

Simple
Reflection
Motivational Interviewing Skills
Shift
Focus
Listen
Reflectively
Roll with
Resistance
Express
Empathy
Side with
the Negative
Develop
Discrepancy
Open-Ended
Questions
Reframing
Avoid
Arguments
Affirm

Simple Reflection
Respond to resistance with
nonresistance by repeating the patient's
statement in a neutral form

Shift Focus
Help the patient shift focus away from
obstacles and barriers

Roll with Resistance
Actively involve the person in the
process of problem solving

Side with the Negative
Take up the negative voice in the discussion

Open-Ended Questions
Solicit additional information in a neutral way

Listen Reflectively
Check rather than assume that you know
what is meant

Express Empathy
Empathy communicates acceptance

Develop Discrepancy
Encourage the patient to see the difference
between their current situation and their
hopes for the future

Reframing
Use a new and positive interpretation of
negative information from the patient

Avoid Arguments
They are counterproductive
and breed defensiveness

Affirm
Support and promote self-efficacy

Motivational Interviewing Steps:
A Practical Approach

Establish Rapport and Build a Therapeutic Alliance

Set a Collaborative Agenda for Remission and Recovery

Assess Importance

Assess Importance
Examine the good things and the not-so-good
things about the current situation
(e.g., patient not taking oral medication regularly)

Assess Importance
Explore Personal Importance as it Pertains to the Individual

Assess Importance
Compare good vs not-so-good
(ownership of problems)

Assess Importance
Discuss Short-Term and Long-Term Goals as
Defined by the Patient

Assess Importance
Discuss Discrepancies with Desired and Achievable
Goals in Short and Long-term

Assess Importance
Openly discuss discrepancies between
physician and patient perspectives

Assess Importance
Summarize and Review Periodically

Assess Importance
Ask for Decision

Assess Importance
Ask for Decision
Assist patient in making a decision
that reflects his/her perspectives,
goals and knowledge

Assess Importance
Ask for Decision
Review Goals and Provide
Continuous Support for Self Efficacy

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Editor's Notes