UTAH MEDICAID DUR REPORT

JANUARY 2021

LONG-ACTING INJECTABLE
&
ORALLY DISINTEGRATING
SECOND GENERATION ANTIPSYCHOTICS
Report Finalized in December 2020
Report Presented in January 2021

Drug Regimen Review Center

Valerie Gonzales, Pharm.D., Clinical Pharmacist

Lauren Heath, Pharm.D., MS, BCACP, Assistant Professor
Vicki Frydrych, B.Pharm., Pharm.D., Clinical Pharmacist
Joanne LaFleur, PharmD, MSPH, Associate Professor

University of Utah College of Pharmacy

Copyright © 2021 by University of Utah College of Pharmacy
Salt Lake City, Utah. All rights reserved

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Contents
Introduction ............................................................................................................................................................ 4
Table 1. Long-Acting Injectable SGAs, FDA Indicated Disorders ........................................... 4
Table 2. ODT Antipsychotics, FDA Indicated Disorders ............................................................ 5
Methods .................................................................................................................................................................... 5
A. Long-Acting, Injectable Second-Generation Antipsychotics........................................................ 6
Diagram 1. Administration Frequency for LAI Products .......................................................... 7
Administration of early doses ................................................................................................................. 8
A.1. Concomitant Use of LAI and Oral Antipsychotics ........................................................................ 8
When initiating LAI antipsychotics ....................................................................................................... 8
If a missed dose occurs .............................................................................................................................. 9
When metabolism modifiers are prescribed ..................................................................................... 9
Management of Breakthrough Psychosis ........................................................................................ 10
A.2. Additional Tables and Considerations for LAI Products ....................................................... 11
Switching from Other LAIs .................................................................................................................... 11
Table 3. Product Prescribing Information Regarding Switching Therapies .................. 11
Unique Safety Warnings for SGA LAIs ............................................................................................... 12
Table 4. Second Generation, LAI Antipsychotics and Labeled Dosing ............................. 13
Table 5. Pharmacokinetics for LAI SGAs ...................................................................................... 15
A.3. Place in Therapy .................................................................................................................................... 17
Overview of Potential Advantages and Disadvantages of LAI Antipsychotics .................. 17
Place in Therapy per Clinical Guidelines .......................................................................................... 18
For Schizophrenia ................................................................................................................................. 18
For Bipolar I Disorder ......................................................................................................................... 19
Pediatric Use ............................................................................................................................................... 19
B. ODT Products .............................................................................................................................................. 20
B.1. ODT Product Description ................................................................................................................... 20
Table 6. ODT Second Generation Antipsychotics, Approved Indications ...................... 20
Table 7. ODT Product Pharmacokinetic Information ............................................................. 21
B.2. Place in Therapy for ODT Products ................................................................................................ 22
Adherence or Compliance ...................................................................................................................... 22

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 Further Information Regarding Rapid Mitigation of Acute Agitation/Aggression
Associated with Various Psychiatric Disorders ............................................................................. 23
Prior Authorization (PA) Considerations ................................................................................................. 25
Summary ............................................................................................................................................................... 27
References ............................................................................................................................................................ 28
Appendix A: Literature Searches ................................................................................................................. 32
Appendix B: Treatment Guidelines Addressing Rapid Mitigation of Acute
Agitation/Aggression ....................................................................................................................................... 33

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Introduction
This document compliments the December 2020 DUR report, Newer Oral Antipsychotics, that reviewed
second generation antipsychotics (SGAs *) and their place in therapy, with focus on 3 newer drug
moieties. This report describes considerations regarding the SGA long-acting injectable (LAI) and orally
disintegrating tablet (ODT) formulations, their place in therapy according to guideline
recommendations, potential advantages, and unique features or directions for use.

LAI antipsychotics offer the potential for improved adherence with less frequent dosing intervals
compared to daily oral regimens. These agents must be administered directly by a healthcare provider.
The 8 available LAI SGA products are shown in Table 1; all are intramuscular (IM) injections except the
subcutaneous product, Perseris. Each LAI SGA is approved for use in schizophrenia. Additionally, Invega
Sustenna is approved for schizoaffective disorder; and Abilify Maintena and Risperdal Consta are
approved for bipolar I disorder.1-8 None are FDA labeled for use in the pediatric population. Labeling
recommendations for initiation of LAI therapy vary. Invega Trinza is indicated for patients who have
received at least 4 months of Invega Sustenna therapy. For other LAIs, patients should have tolerated
the corresponding oral antipsychotic prior to initiation (or risperidone for Invega Sustenna).
Supplementation with an oral antipsychotic is required during the initiation of Abilify Maintena,
Aristada, and Risperdal Consta. Aristada Initio is used as a single loading dose for initiation of Aristada,
or as a single supplementation dose following a missed Aristada dose.

Table 1. Long-Acting Injectable SGAs, FDA Indicated Disorders 1-8, a

LAI Product (administration interval)
Aripiprazole Aripiprazole Olanzapine Paliperidone palmitate Risperidone
lauroxil pamoate

Abilify Aristada Zyprexa Invega Invega Risperdal Perseris

Maintena (monthly – Relprevv Sustenna Trinzac Consta (monthly)
(monthly) 2 months) (2-4 weeks) (monthly) (3 months) (2 weeks)
Aristada
Initiob
Bipolar I disorder X X
Schizophrenia X X X X Xd
X X
Schizoaffective X
disorder
a
Per labeling, Abilify Maintena has not been studied in patients 18 years or younger, and the other LAIs have not
been established in patients less than 18 years of age.
b
Aristada Initio is only to be used as a single dose, as part of the loading dose phase for initiation of Aristada or as a
single supplementation dose in the event of a missed dose of Aristada.
c
Invega Trinza is for patients who stabilized onto at least 4 months of Invega Sustenna.
d
Prescribing information recommends against use in the pediatric population.

Four ODT antipsychotics are available as shown in Table 2. These formulations were developed to
increase usability in patients with difficulty swallowing tablets. Experts note that the ODT formulation
may also help circumvent discreet non-compliance (“cheeking”).9 The ODT antipsychotics have the same
indications as their conventional-tablet counterpart but are quickly dissolved once placed on the

*
For this report, we will use the terminology of SGA, with third generation antipsychotics included among SGAs.

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tongue— usually dissolved within 1 minute—and the dissolution contents can be more easily swallowed
without liquid. Aside from other solid dosage forms, 3 of these ODT drug moieties are also available as
oral solutions (aripiprazole generic solution, clozapine as a brand product [Versacloz], and risperidone
generic solution), while olanzapine is unavailable as an oral solution.

Table 2. ODT Antipsychotics, FDA Indicated Disorders10-15

Aripiprazole Clozapine Olanzapine Risperidone
ODT ODT ODT ODT
Zyprexa Zydis Generic
Generic Generic
and Generic
Bipolar I disorder (acute X X (also for X
treatment for manic/mixed maintenance
episodes) treatment)
Schizophrenia X X (for treatment resistant X X
(and Schizoaffective disorder for disease, and for
clozapine) schizophrenia/schizoaffective
suicidal behavior)
Tourette’s disorder X
Major Depressive Disorder, X
Adjunct
Autism-related irritability X X
Abbreviation: ODT, oral disintegrating tablet

The Utah Medicaid preferred drug list (PDL) includes the following antipsychotic medications as
preferred status:

 LAIs: Abilify Maintena, Aristada, Invega Sustenna, Invega Trinza, Perseris

 ODTs: olanzapine ODT
 Additional oral forms: aripiprazole tablet, clozapine tablet, Latuda (lurasidone), olanzapine,
quetiapine, quetiapine ER, risperidone solution and tablet, Saphris (asenapine), and ziprasidone

Potential prior authorization (PA) criteria considerations for LAI and ODT SGAs are consolidated on page
25. Currently, PA criteria are in place for the use of antipsychotics in children less than 6 years of age,
and for combination antipsychotic therapy in patients under 20 years of age.

Methods
Product labeling was referenced for information regarding the approved indication(s), directions for use,
pharmacokinetic information, and safety warnings. Additional information was obtained from FDA drug-
approval reviews to supplement prescribing information; these were accessed at the following FDA
website: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Product labels (ie, package
inserts) were obtained from the drug sponsor’s website for the brand product and from the dailymed
website (https://dailymed.nlm.nih.gov/dailymed/) for generic formulations. For information regarding
the Tmax of the ODTs, a literature search in Embase (translated to Ovid-Medline) was used to find
additional information beyond that provided in product labeling or FDA reviews: (disinteg*:ti OR odt*:ti
OR dissol*:ti) AND (olanzapine:ti OR aripiprazole:ti OR risperidone:ti OR clozapine:ti).

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For information regarding the place in therapy for ODTs and LAI antipsychotics, specific mention
referring to LAI or ODT use was extracted from clinical practice guidelines for the management of
schizophrenia, bipolar disorder, acute aggression, and autism that were identified in the December 2020
DUR report. Additional guidelines were reviewed particularly for disruptive and aggressive behaviors in
youth, and for the management of agitation and psychosis in patients with dementia.

Literature searches for systematic reviews were developed to further determine whether there was
other information that would differentiate the place of therapy of LAIs and ODT antipsychotics as a class
from the conventional oral formulation. Appendix A includes the searches executed in OvidMedline and
Epistemonikos using key words for active ingredients and phrases for ODT and LAI formulations. A
combination of independently derived filters and a McMaster University filter16 were used to identify
systematic reviews in Ovid-Medline.

A. Long-Acting, Injectable Second-Generation Antipsychotics

Products containing aripiprazole include Abilify Maintena and Aristada, with Aristada as the pro-drug,
aripiprazole lauroxil. Both products are indicated for schizophrenia, but Abilify Maintena has the
additional indication for bipolar I disorder. Abilify Maintena is a monthly injection, whereas Aristada can
be dosed monthly, every 6 weeks, or every 2 months. The single olanzapine-containing LAI, Zyprexa
Relprevv, is administered every 2 or 4 weeks. The newer risperidone LAI, Perseris, differs from Risperdal
Consta (IM, every 2 weeks) in that it is a monthly subcutaneous injection that does not require oral
overlap during initiation. Invega Sustenna (dosed monthly) and Invega Trinza (dosed every 3 months)
contain paliperidone which is an active metabolite of risperidone. Paliperidone is influenced less by the
CYP2D6 enzyme compared to risperidone, which can be a clinical advantage for reducing some drug-
drug interactions.17 However, both risperidone and paliperidone are influenced by strong CYP 3A4
and/or P-glycoprotein inducers. Aripiprazole-containing LAIs are also metabolized by CYP3A4 and 2D6
enzymes. Product labeling should be referred to for dose adjustment recommendations related to CYP
enzyme effects with these LAI medications.

Currently, Risperdal Consta (risperidone) and Zyprexa Relprevv (olanzapine), are listed as non-preferred
on the Utah Medicaid PDL, while the other LAIs are preferred [Abilify Maintena (aripiprazole), Aristada
products (aripiprazole lauroxil), Invega Sustenna/Trinza (paliperidone), and Perseris (risperidone)].

PA Consideration

• May consider a PA requirement for Risperdal Consta, to have a prior trial/failure of Invega
Sustenna or Perseris, or provide clinical rationale (eg, bipolar I indication) for the use of
Risperdal Consta instead of the PDL preferred LAIs (Invega Sustenna or Perseris) which, like
Risperdal Consta, are options approved for patients with schizophrenia who demonstrate
tolerability to oral risperidone.

Prior to initiation of LAI antipsychotics, patients should demonstrate tolerability to the corresponding
oral agent, while Invega Trinza should specifically be preceded by at least 4 months of adequate
treatment with Invega Sustenna. Prior to initiation of Invega Sustenna, demonstration of tolerability to
either oral paliperidone or oral risperidone is acceptable. With respect to Perseris, patients stable on
oral risperidone <3 mg/day or >4 mg/day may not be candidates for this medication since plasma levels

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would either be too high or low, respectively. Perseris 90 mg and 120 mg per month correspond to
3 mg/day and 4 mg/day of risperidone, respectively, based on average plasma concentrations.8

PA Consideration

• May consider requiring the prescriber’s attestation or documentation of the patient’s prior
tolerance to the corresponding active ingredient (or risperidone for Invega Sustenna) prior to
initiation of the LAI.
• For Invega Trinza, consider the requirement for at least 4 consecutive months of Invega
Sustenna therapy immediately preceding its initiation, with the last two Sustenna doses being
the same and within the range of 78 – 234 mg/month. The labeling for the product recommends
establishing a consistent Sustenna maintenance dose prior to conversion to Trinza. Initial dosing
for Trinza is based on the Sustenna lead-in dose, but a conversion for Sustenna 39 mg per month
is not provided/accommodated with the available Trinza strengths.5

Although assessment of plasma levels are not required by labeling or guidelines, an expert review
describes the clinical utility of measuring antipsychotic plasma levels to help inform the conversion to
LAI therapy.17 Laboratory assessment can help to more accurately divulge the patient’s antipsychotic
exposure rather than going off subjective self-report or the patient’s prescribed oral dose, considering
high-rates of partial adherence and that patients may be selected for LAI specifically to address
adherence.17 Plasma level monitoring is a current area of study, but there is a 2017 guideline18 and a
meta-analysis that we are aware of with information regarding therapeutic plasma levels.19
The starting maintenance dose for LAI products is either based on corresponding target oral
antipsychotic doses (as for Aristada, Zyprexa Relprevv, and Perseris), or based on general dosage ranges
provided for the indications (as for Abilify Maintena, Invega Sustenna, and Risperdal Consta); see Table
4 on page 13 for product dosing. These agents must be administered directly by a healthcare provider to
ensure adequate reconstitution and mixing procedures, and proper injection and aseptic techniques.

Diagram 1 depicts the dosing intervals for maintenance therapy with LAI products. Each interval
corresponds to a certain milligram dosage as summarized in Table 4 of page 13.

Diagram 1. Administration Frequency for LAI Products

Dose 1 month 2 months 3 months

Abilify Maintena (ARI) Monthly
Monthly
Aristada (ARI-L) Q 6 weeks
Q 2 months
Q 2 weeks
Zyprexa Relprevv (OLN)
Q 4 weeks
Invega Sustenna (PALI) Monthly
Invega Trinza (PALI) Q 3 months
Risperdal Consta (RIS) Q 2 weeks
Perseris (RIS) Monthly
Abbreviations: ARI, aripiprazole; ARI-L, aripiprazole lauroxil; LAI, long-acting injectable; OLN,
olanzapine; PALI, paliperidone; Q, every; RIS, risperidone

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Administration of early doses in order to avoid missing a dose is addressed in package inserts for
Aristada, Invega Sustenna, and Invega Trinza as provided below. For other products (Perseris, Risperdal
Consta, Zyprexa Relprevv), there is no mention of a shorter interval than the general recommended
dosing frequency.

• Abilify Maintena (monthly): labeling states that the 400 mg dosage should be administered no
sooner than 26 days after the previous injection1
• Aristada (monthly, every 6 weeks, or every 2 month): the recommended dosing frequency
should be maintained, but in the event a needed early dose, the dose should occur no earlier
than 14 days after the previous injection.3
• Zyprexa Relprevv (every 2 or 4 weeks): early doses are not described in the labeling; the shortest
dosing frequency is every 2 weeks.4
• Invega Sustenna (monthly): The time point at which an early dose can be administered depends
on whether the patient is in the loading dose phase or maintenance phase.
o Loading phase: To avoid a missed dose, the second loading dose can be given as early as
3 days after the first dose. The third dose should be given within 5 weeks of the first
dose, regardless of the timing of the second dose.6
o Maintenance doses: Subsequent monthly injections can be injected 7 days before the
monthly time point.6
• Invega Trinza (every 3 months): Only if necessary, doses may be administered up to 2 weeks
early.5
• Risperdal Consta (every 2 weeks): early dosing is not described in the labeling.
• Perseris (monthly): early dosing is not described in the labeling, but it states to not administer
more than 1 dose per month.8

A.1. Concomitant Use of LAI and Oral Antipsychotics

When initiating LAI antipsychotics, some products require overlap with an oral antipsychotic during
the first several weeks while the injectable agent rises to therapeutic plasma concentrations:

• Overlap for the first 2 weeks while on Abilify Maintena with either 10-20 mg/day of oral
aripiprazole or with the patient’s current oral antipsychotic (provided the patient has
demonstrated tolerability to aripiprazole in the past).1
• Overlap the single Aristada Initio dose with one dose of 30 mg oral aripiprazole for initiation
onto Aristada; Aristada Initio can be administered on the same day as Aristada or up to 10 days
before.2
• Overlap Aristada (if initiated without using the Initio product) and Risperdal Consta for the first
3 weeks with oral aripiprazole and oral risperidone, respectively.3,8
o Review articles note that therapeutic levels with Risperdal Consta may not be reached
until 4 weeks after the initial injection based on its pharmacokinetic profile; thus oral
overlap may be needed out to 4 weeks from its initiation.17,20

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Products that do not require overlap with an oral product during their initiation include the following:

• Perseris: A loading dose or overlap with oral risperidone is not recommended, according to the
package insert.21
• Invega Trinza: At least 4 months of Invega Sustenna should immediately proceed the initiation
of Invega Trinza as opposed to an oral product. Invega Trinza is initiated at the next 1-month
dose due for Sustenna.6
• Zyprexa Relprevv: While olanzapine plasma concentrations were slightly lower during the first
injection interval of Zyprexa Relprevv compared to concentrations with the corresponding oral
dose, the concentration remained within the therapeutically effective range during initiation
such that oral supplementation was generally not necessary in clinical trials.4
• While oral overlap with Invega Sustenna is not required, the direction is to gradually discontinue
the patient’s oral antipsychotic at the time of Invega Sustenna initiation; thus, the potential for a
short course of overlap is possible but vague as the labeling does not explicitly state for the oral
antipsychotic to be completely discontinued before the day of the first injection. Of note is that
the initiation regimen of Invega Sustenna was designed to rapidly attain steady-state
concentration without the use of oral supplementation per package insert.7

Based on a US survey to asses clinical practices and expert opinion, while experts do refer to labeled
directions for use, they may also consider tapering off the oral agent over a period of 1–3 weeks from
the LAI start date based on patient needs and the product used.22

Loading doses (ie, larger LAI initial doses than maintenance doses) are employed during the initiation of
Zyprexa Relprevv (during the first 8 weeks4), Invega Sustenna (2 loading doses in the first week6), and
when using Aristada Initio for Aristada initiation. In the event that products are not loaded adequately,
patients may have a suboptimal response and may need oral antipsychotic coverage.17

If a missed dose occurs, the patient should reinitiate the following LAIs with supplemental oral
antipsychotic:

• If more than 5 or 6 weeks have elapsed since the last dose of Abilify Maintena1
• If more than 6, 8, or 10 weeks have elapsed (depending on that patient’s ongoing dose regimen)
since the last dose of Aristada3 (see package insert for further details)
• Although not discussed in the package insert, oral supplementation would likely be needed with
Risperdal Consta, especially if more than 4-6 weeks have elapsed from the last dose (steady
state concentration is maintained for up to 4 to 6 weeks after the last dose and there is a lag
time of 3 weeks for the release phase of this LAI)7

When metabolism modifiers are prescribed: Labeling for Risperdal Consta and Perseris includes the
option to either supplement with oral risperidone or to increase the LAI dose in the event of
concomitant use with a strong CYP 3A4 inducer.8,21 Effects from CYP 2D6 inhibitors (eg, fluoxetine,
paroxetine) should also be factored in, if applicable.

o Co-administration of CYP 3A4 enzyme inducers (eg, carbamazepine, phenytoin, rifampin,

phenobarbital) with risperidone is expected to decrease risperidone plasma concentrations and
the active metabolite 9-hydroxyrisperidone.8,21 CYP 2D6 is a major metabolic pathway for
risperidone.8

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The following prescribing information is provided for other products regarding CYP inducer-drug
interactions:

• Abilify Maintena is not recommended for use with more than 14 days of a strong CYP 3A4
inducer.1
• Aristada: With more than 2 weeks of use with a strong CYP 3A4 inducer, an increase in the
441 mg dose, to 662 mg, should be considered, and no dose adjustments are required for
patients on the 662 mg, 882 mg, or 1064 mg dosages.3
• Invega Sustenna and Invega Trinza: Co-administration with strong CYP3A4/P-glycoprotein (P-gp)
inducers should be avoided; otherwise, consider using paliperidone extended-release tablets.6
• Zyprexa Relprevv: strong inducers of CYP1A2 (eg, carbamazepine) can increase the clearance of
olanzapine by 50%; however, specific recommendation regarding oral supplementation after
exhausting increased dosing options is not provided in the product prescribing information.4

Management of Breakthrough Psychosis

Residual symptoms can persist until the LAI dosage is optimized and/or until the steady state blood
levels are achieved.22,23 It is also possible a breakthrough psychosis episode (BPE) or symptom worsening
may occur while a patient is in the maintenance phase. Prescribers should rule out or address medical
illness, other psychiatric comorbidities or stressors, substance use, and optimize non-pharmacological
treatments if possible. Another contributing factor may include plasma levels below therapeutic range,
with or without non-adherence. Symptomatic patients may present to prescribers other than their LAI
prescriber (eg, emergency room). If possible, the provider should determine the medication type and
date of LAI administration to inform weather therapeutic levels have been achieved.23
When surveyed about the timing of subsequent LAI doses, US psychiatric experts agreed that important
factors for consideration were package insert recommendations, whether symptoms occurred before
the end of the dosing interval, type of symptoms involved, whether there was initial symptom
improvement after starting the LAI, pharmacokinetic properties of agents, and presence of side
effects.22 For residual or breakthrough positive symptoms in schizophrenia (eg, hallucinations, delusions,
and aggression) or psychotic symptoms in bipolar disorder, experts may consider either switching to a
medication approved for treatment-resistant disease, switching to an alternative LAI with a different
active ingredient, or adding on the same oral antipsychotic to the LAI.22
Guidance from the Florida Center for Behavioral Health Improvement and Solutions group supports
various options based on the provider’s clinical judgment for the management of breakthrough
psychotic symptoms as originally presented by Correll et al.23,24 When a provider evaluates that
additional antipsychotic exposure is needed due to the severity of the patient’s symptoms the following
options may be considered: address missed LAI doses appropriately (see product labeling), increase the
LAI dosage or shorten the LAI interval (may include off-label doses/intervals based on expert opinion), or
for fast symptom control consider low dose oral supplementation preferably with the same
antipsychotic corresponding to the LAI; yet, caution should be exercised using oral supplementation
since evidence on long-term combined use is limited. The patient should be monitored closely,
evaluating symptoms after 1 to 2 weeks and then as appropriate. If symptoms stabilize, the oral
antipsychotic should be discontinued slowly after 2 or more weeks from its initiation. For persistent
symptoms, an increase in the oral antipsychotic can be considered or alternative options (eg, shorten

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the LAI interval, increase LAI dose, change the oral antipsychotic, switch the LAI), all while trying to
optimize the patient’s regimen and monitoring the patient closely during dose adjustments.23,24

A.2. Additional Tables and Considerations for LAI Products

Switching from Other LAIs

Aside from Invega Sustenna and Invega Trinza, there is no instruction provided in the package inserts for
other LAIs about conversion from one LAI to another. Such practice of switching from one LAI directly to
another is complicated by the long half-lives of LAIs, dosing recommendations for some that is based on
oral target doses, and unique pharmacokinetics (for example Risperdal Consta and Aristada peak
concentrations can occur 3 weeks or later after injection). For Invega Sustenna, the package insert states
that patients switching from a different LAI antipsychotic currently at steady-state, can be initiated onto
Sustenna at the next scheduled injection of the previous LAI without the one-week loading dosages.
Without specificity with respect to the proceeding LAI, this direction does not clearly account for unique
pharmacokinetics of various products; thus, it is debatable whether this suffices as enough information
of how to best convert between each possible LAI product. Moreover, the labeling states in another
section, “There are no systematically collected data to specifically address switching patients …from
other antipsychotics to INVEGA SUSTENNA.”6 Table 3 summarizes product switch information from the
product prescribing information.

A 2016 survey of psychiatric clinical or research experts on LAI therapy found conflicting responses
regarding the approach to switching between LAIs.22 Nonetheless, experts would generally consider
starting the new LAI at the next dose due for the previous LAI, with or without oral antipsychotic overlap
depending on the time to therapeutic levels of the old and new LAI. Yet, experts stressed first
establishing tolerability with the oral formulation if the patient is naive to the LAI drug molecule.22

Table 3. Product Prescribing Information Regarding Switching Therapies 1-8

Switching from an ORAL agent Switch from another LAI
 All product inserts (except that for Invega Trinza) describe that the patient should have demonstrated
tolerability to the corresponding oral active ingredient prior to starting the LAI (oral risperidone also
acceptable for Invega Sustenna)
Overlap with an oral antipsychotic, aripiprazole No information
Abilify
Maintena
(ARI)

or other, for the first 14 days of Abilify

Maintena initiation

Overlap with oral aripiprazole during the

No information
Aristada
(ARI-L)

initiation phase is directed, for the 1st day if

Note that the recommended dose for Aristada is based on
the Initio product also used, or for first 21 days
total daily dosages of oral aripiprazole. If switching from
without the Initio product
Aristada straight to a different LAI at the 1 month time-
point, there could be issues since Aristada reaches peak
concentration after 1 month.
No information
Relprevv
Zyprexa

(OLN)

Overlap with another antipsychotic during the initiation phase of Zyprexa Relprevv is generally not needed;
dosing is based on corresponding target oral olanzapine doses. Moreover, there is no systematically
collected data to address switching patients over from other antipsychotics.

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Table 3. Product Prescribing Information Regarding Switching Therapies 1-8
Switching from an ORAL agent Switch from another LAI
Gradually discontinue the patient’s oral PI states that for patients switching from a different LAI
Invega Sustenna
(PALI)
antipsychotic during the time of initiating antipsychotic currently at steady-state, Invega Sustenna
Invega Sustenna. can be initiated at the next scheduled injection for the
previous LAI without the one-week loading dosages; yet,
The initiation regimen with loading doses of it is unclear if the potential safety issues were considered
Invega Sustenna was designed to rapidly attain with respect to each potential LAI switch and unique LAI
steady-state concentration without the use of pharmacokinetics per product, as the PI also notes no
oral supplementation. data to specifically inform switching patients from other
antipsychotics.
Invega Trinza is specifically approved for patients on at least 4 months of Invega Sustenna therapy
Invega
Trinza
(PALI)

proceeding its initiation

Continue previous antipsychotic for 3 weeks No information

Risperdal Consta
(RIS)

after the first injection to compensate for the

delayed release of risperidone (other
references note that 4 weeks of overlap with
an oral product may be need17,20)
No systematically collected data addresses switching patients from other antipsychotics to Risperdal Consta

No information
Perseris
(RIS)

Supplementation with an additional antipsychotic during the imitation phase of Perseris is not
recommended (ie, recommended against)
Abbreviations: ARI, aripiprazole; ARI-L, aripiprazole lauroxil; LAI, long-acting injectable; PALI, paliperidone; PI, package
insert; PK, pharmacokinetics; RIS, risperidone

Unique Safety Warnings for SGA LAIs

Warnings for SGA LAIs that are additional to those in common with the oral form are as follows:

 Zyprexa Relprevv has a black box warning regarding the risk of severe sedation and possible
coma (ie, post-injection delirium/sedation syndrome). Thus, a REMS program is in place with
distribution restricted to certified prescribers/clinics/pharmacies following training activities.
Even though this severe reaction occurs infrequently, in <0.1% of injections and in about 2% of
patients during clinical trials,4 the labeling requires a 3 hour observational period in the clinic
following administration so that emergency response by the healthcare staff can be immediately
employed if such reaction occurs.
 Aristada Products: “Medication errors, including substitution and dispensing errors, between
ARISTADA and ARISTADA INITIO could occur.”3 Aristada Initio is only for use as a single dose to
initiate Aristada, or as a supplemental dose in the event of a missed Aristada injection (eg, if 2
weeks or more late, depending on the dosage); whereas, Aristada is administered monthly,
every 6 weeks, or every 8 weeks.3
 Risperdal Consta: Osteodystrophy and tumors (eg, adenoma, adenocarcinoma, and
adrenomedullary pheochromocytoma) in animals were observed following exposure to
Risperdal Consta, but the risk to humans is not fully known.7

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Table 4 provides the recommended dosing and strengths available for LAI SGAs. Table 5 provides
information regarding pharmacokinetics and dose modifications for special populations.

Table 4. Second Generation, LAI Antipsychotics and Labeled Dosing1-8,21

Dosage Forms Indication/Dosing
(Approval Year)
Aripiprazole Indications: Schizophrenia in adults; and maintenance monotherapy for bipolar I in
adults
Abilify Maintena
o For patients known to tolerate aripiprazole; otherwise, establish tolerance prior to
Powder for
starting LAI-ARI; may take up to 2 weeks to determine tolerability to ARI
reconstitution;
300-mg or 400-mg: Administer IM, monthly, into deltoid or gluteus by healthcare professional
 pre-filled, dual o Maintenance dose: 160-400 mg monthly. Initiate at 400mg monthly. Should be on
chamber syringe oral ARI or other antipsychotic for the first 14 days of LAI initiation
 single-dose vial o Maximum dose: 400 mg monthly, no sooner than 26 days after previous dose
(2013) o Dose reductions (eg, 160-300 mg per month) based on adverse reactions and
required for poor CYP2D6 metabolizers or if taking concomitant CYP3A4 inhibitors
or CYP2D6 inhibitors for more than 14 days
Note: The SS Cmax with the 400 mg/month dose approximates SS plasm levels
achieved with oral ARI 20–30 mg/day; and the SS trough with 400 mg/month
approximates SS plasma levels with oral ARI 15–20 mg/day25
Aripiprazole lauroxil Indication: Schizophrenia in adults
o Establish oral aripiprazole tolerability first which may take up to 2 weeks
Aristadaa
Administer IM, monthly to every 2 months, into deltoid or gluteus (depending on dose)
Pre-filled syringes
given by healthcare professional:
of 441 mg, 662 mg,
o Initiation options include:
882 mg, or 1064 mg
 Option #1: Co-administer Aristada Initio 675 mg and 30 mg oral aripiprazole with
(2015)
the first Aristada injection (administer Aristada into a different site either the same
day as Aristada Initio or up to 10 days after).
 Option #2: 21 days of oral aripiprazole in conjunction with the first Aristada
Aristada Initio
injection.
Pre-filled syringe,
 Aristada can be initiated according to patient’s oral dose:
675 mg
Oral ARI IM Aristada; injection site
(2018)
10mg/day 441mg/month; deltoid or gluteus
15mg/day 662mg/month; 882mg/6wks; or 1064mg/2months; gluteus
≥20mg/day 882mg/month; gluteus
o Maximum: 882 mg administered monthly, or 1064 mg every 2 months
o Dose adjustments required for CYP2D6 poor metabolizers and for patients taking
CYP3A4 inhibitors, CYP2D6 inhibitors, or CYP3A4 inducers for more than 2 weeks
Olanzapine Indication: Schizophrenia in adults
pamoate o Establish tolerability with oral olanzapine prior to initiating treatment.
Zyprexa Relprevv Administer IM, every 2 or 4 weeks; into the gluteus by a healthcare provider
Powder for o Dose based on target oral olanzapine dose
suspension: Oral Zyprexa Relprevv: initial loading dose X 8 weeks; and dose
210 mg, 300 mg, olanzapine thereafter
and 405 mg vials dose target
(2009) 10 mg/day 210 mg/2 wks or 405 mg/4 wks; followed by 150mg/2 wks or
300mg/4 wks
Restricted 15 mg/day 300 mg/2 wks; followed by 210mg/2 wks or 405mg/4 wks
distribution (REMS) 20 mg/day 300 mg/2 wks; then 300 mg/2 wks
o Maximum 405 mg/4 wks, or 300mg/2 weeks

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Table 4. Second Generation, LAI Antipsychotics and Labeled Dosing1-8,21
Paliperidone Indications: Schizophrenia in adults; and schizoaffective disorder in adults as
palmitate monotherapy and as an adjunct to mood stabilizers or antidepressants
o Establish tolerability to oral paliperidone or risperidone prior to initiation
Invega Sustenna
Suspension, Administer IM, monthly, into deltoid or gluteus by a healthcare provider
prefilled syringes, o Maintenance dose: 39-234 mg monthly for schizophrenia; 78-234 mg monthly for
39 mg, schizoaffective disorder
78 mg, 117 mg, o Maximum: 234 mg monthly
156 mg, and 234mg o Initiate at 234 mg on day 1, then a dose of 156 mg between day 4 to 8; monthly
(2009) maintenance doses are used thereafter
 “initiation plasma levels with INVEGA SUSTENNA® were within the exposure
range observed with 6-12 mg extended-release oral paliperidone”
Indication: Schizophrenia, as a follow on option to at least 4 months of treatment with
Invega Trinza Invega Sustenna
Suspension,
prefilled syringes of Administer IM, once every 3 months, into the deltoid or gluteus by a healthcare
273 mg, 410 mg, provider only
546 mg, or 819 mg o 273 mg to a maximum of 819 mg every 3 months depending on the previous dose
(2015) of Invega Sustenna:
Sustenna Last Dose Initiate Trinza at the following dose
78 mg 273 mg
117 mg 410 mg
156 mg 546 mg
234 mg 819 mg
There is not a conversion for the 39 mg dose of Sustenna
Risperidone Indication: Schizophrenia; and for monotherapy or adjunctive therapy to lithium or
valproate for bipolar I disorder
Risperdal Consta o Establish tolerability with oral risperidone prior to initiating treatment.
Vials for Administer IM, once every 2 weeks into the deltoid or gluteus by a healthcare provider
reconstitution: o 25 mg to 50 mg every 2 weeks
12.5mg, 25mg, o Give oral antipsychotic concomitantly for the first 3 weeks of initiation; titrate
37.5 mg, or 50 mg upward no more than every 4 weeks and assess response no earlier than 3 weeks
(2003) after injection
Risperidone Indication: Schizophrenia in adults
o Establish tolerability with oral risperidone. Patients stable on oral risperidone
Perseris <3 mg/day or >4 mg/day may not be candidates
Prefilled syringe Administer subQ, monthly, into the abdomen by a healthcare provider only
reconstitution kit, o Initiate at 90 or 120 mg without supplemental oral risperidone
90 mg or 120 mg  Perseris 90 mg ≅3 mg/day oral risperidone
(2018)  Perseris 120 mg ≅4 mg/day oral risperidone
o Maximum of 120 mg injection per month
a
Aristada 441 mg, 662 mg, 882 mg and 1064 mg doses correspond to 300 mg, 450 mg, 600 mg and 724 mg of
aripiprazole, respectively
Abbreviations: ARI, aripiprazole; IM, intramuscularly; LAI, long-acting injectable; REMS, Risk Evaluation and
Mitigation Strategy; SS, steady state; subQ, subcutaneously

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Table 5. Pharmacokinetics for Long Acting Injectable SGAs1-8
Product (a) Half-Life (T1/2) Elimination Special Populations
Dosing (b) Time to steady State (tSS)
Frequency
Aripiprazole
T1/2: 30 or 47 days for 300mg Hepatic (major No dose adjustments for renal or hepatic
Abilify
and 400mg dose, route): CYP 2D6 impairment.
Maintena
respectively and 3A4
Dose reduce (to 160 – 300 monthly) based
Monthly tSS occurs by the 4th Renal: <1% of on adverse reactions, and for poor
monthly dose the dose CYP2D6 metabolizers or if taking
concomitant CYP3A4 inhibitors or CYP2D6
Tmax: 4-7 days Active
inhibitors for > 14 days (see package
metabolite is
SS Cmax with 400mg dose insert); not recommended for use with
dehydro-ARI
approximates SS levels >14 days of a strong CYP 3A4 inducer.
achieved with oral ARI 20–30
mg/day; and the trough
approximates SS plasma
levels with oral ARI 15–20
mg/day25
Aripiprazole
T1/2: 54 to 57 days Hepatic (major No dose adjustments for mild to severe
lauroxil
route): CYP 2D6 renal or hepatic impairment.
Aristada tSS by 4th month
and 3A4
Dose adjustments required for CYP2D6
In conjunction with either of
Monthly to Active poor metabolizers and for patients taking
the 2 loading dose regimens
every 2 metabolite is CYP3A4 inhibitors, CYP2D6 inhibitors, or
using Intio or oral ARI,
months dehydro-ARI CYP3A4 inducers for more than 2 weeks
relevant plasma levels are
(see package insert)
reached by 4th day
ARI Tmax: 37-48 days after a
single dose of
441 mg; and median Tmax
after the 4th dose (at 28 day
interval) of 21- 28 days for
441-662 mg, and 6 days for
the 884 mg dosag26e
Olanzapine T1/2: 30 days Extensive No renal adjustment necessary, nor for
Zyprexa hepatically hepatic impairment of Childs Pugh
Relprevv tSS by ~3 months metabolized via Classification A or B; use with caution in
CYP 2D6 and Childs Pugh Class C.
Every Tmax: within 1 week 1A2
Start a lower dose (150 mg/4 weeks) in
2 or 4 weeks
patients debilitated; with predisposition
57% and 30% of
to hypotensive reaction; or with
the dose
potentially slower metabolism (eg,
recovered in the
nonsmoking females ≥65 years of age).
urine and feces,
respectively Smoking can contribute to increased
clearance of olanzapine however
increased dosages are not automatically
advised

15 | P a g e
Table 5. Pharmacokinetics for Long Acting Injectable SGAs1-8
Product (a) Half-Life (T1/2)
Dosing (b) Time to steady State (tSS)
Frequency
Paliperidone
palmitate T1/2: 25 to 49 days
Invega
Sustenna tSS approached by first dose
Monthly Median Tmax of 13 days
after single dose; release
lasts for as long as 126 days
Initiation plasma levels were
within the exposure range of
oral ER paliperidone 6-12
mg/day with the loading
regimen
Paliperidone
palmitate T1/2: 84-95 days with deltoid
Invega Trinza injection and 118-139 days
with gluteal injection
Every 3
months Median Tmax of 30-33 days;
release can last as long as 18
months
Risperidone T1/2: 3-6 days
Risperdal
Consta tSS: after 4th injection and
maintained for 4 to 6 weeks
Every 2 weeks after the last dose
There is a 3 week lag time to
the main release of the drug
Risperidone T1/2: 9-11 days
Perseris
tSS: reached by end of the
Monthly 2nd dose and maintained for
4 weeks after last injection
Initial Tmax at 4-6-hours,
and a second peak at 10- to
14-days post-dose
Abbreviation: ARI, aripiprazole; Cmax, maximum concentration; CYP, cytochrome P450 enzyme; ER, extended
release; SSc, steady-state concentration; Tmax, time to peak plasma concentration; tSS, time to steady state
Elimination Special Populations
Renal (80%) and Not recommended in moderate-severe
< 11% via feces; renal impairment (creatinine clearance <
potentially 50 mL/min). In mild renal impairment, use
minor CYP 78 mg maintenance monthly dose.
contribution Has not been studied with severe hepatic
(3A4 and 2D6) impairment
Co-administration with strong CYP3A4/P-
glycoprotein (P-gp) inducers should be
avoided; otherwise, consider using oral
paliperidone.
Mainly renal Not recommended in moderate-severe
(80%) and less renal impairment; for mild renal
than 11% impairment, stabilize first on Invega
through feces; Sustenna then transition to Trinza.
minor CYP Has not been studied with severe hepatic
contribution impairment; no adjustment for mild to
(3A4 and 2D6) moderate impairment.
Co-administration with strong CYP3A4/P-
glycoprotein (P-gp) inducers should be
avoided; otherwise, consider using
paliperidone extended-release tablets.
Use a lower starting dose in renal or
hepatic impairment
Consider dose reduction with the addition
of strong CYP2D6 inhibitors; Consider
Renal: 70% and dose increases with CYP3A4 inducers;
14% via feces additional oral risperidone therapy may
Metabolized by be needed with the use of CYP inducers.
CYP 2D6 (major)
and others may
contribute some
(eg, 3A4)
16 | P a g e
A.3 Place in Therapy

Overview of Potential Advantages and Disadvantages of LAI Antipsychotics

Potential Advantages

• Identification of non-adherence with an LAI antipsychotic is more straight-forward than with oral
antipsychotics when injections are administered by the prescriber’s healthcare team. Clinicians will
be immediately aware of non-adherence when the patient misses their return visit for LAI
administration. Thus, the provider may have a greater window of opportunity to intervene before
symptoms recur.27
• Since adherence can be assessed more objectively from a record of LAI administrations, in contrast
to an oral antipsychotic prescription, it can be easier to discriminate between non-adherence vs.
treatment refractoriness as the cause of relapse or an insufficient response.28
o The potential advantages mentioned above, however, may not apply if LAI products are
dispensed to patients without documentation/accountability of the date administered or
information relayed back to the prescriber.
• Less frequent dosing with LAIs may be easier/preferred for some patients versus daily dosing.27,28
Patients ambivalent toward taking medications (eg, those who may not acknowledge/perceive
benefits from the treatment and/or may not perceive a risk of relapse) or those with
neurocognitive deficits may not reliably take a daily medication, thus, may be better managed with
an LAI.27
• An LAI regimen may increase the interaction between the patient and healthcare staff;28 this may
translate to more opportunities to motivate the patient to stay in therapy, and may help address
side effects or response issues earlier.
• Some observational studies have found that LAI use is associated with reduced relapse frequency
and rehospitalization rates, versus oral antipsychotic therapy, in the treatment of schizophrenia.27
• There is less risk of accidental or deliberate overdose with LAIs if dispensing is restricted to the
healthcare provider, an important consideration particularly for high-risk patients.29

Potential Disadvantages

• The longer time to achieve steady state levels29 can complicate interpretation of patient response
to dose adjustments.27
• May be viewed as having less flexible dose adjustments.29
• Side effects can persist longer after discontinuation of the LAI than with oral medication, thus,
patients should demonstrate tolerability to the oral formulation first; “Nevertheless, caution is
warranted in a patient who has experienced NMS [Neuroleptic malignant syndrome] previously.”27
• There may be some burden involved with scheduling and traveling for LAI administration.
• Barriers for the provider may include insufficient space or personnel to administer LAIs and observe
patients after injection; or inadequate insurance coverage for administration/observation costs,
which may incentivize prescribing of oral formulations.27,30

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Place in Therapy per Clinical Guidelines

For Schizophrenia

The 2020 American Psychiatric Association’s (APA) guideline suggests that patients should receive an LAI
antipsychotic if they prefer such formulation or if the patient has a history of poor or uncertain
adherence. (rated as a weak recommendation, supported by moderate quality of evidence).27 In
addition to the APA guideline, others (RANZCP29, BAP28, NICE31) also recommend that patients receive
LAI antipsychotics if preferred, or as a means to improve or clarify the level of adherence.27 APA authors
comment that the formulation type may influence adherence as ODTs, oral solutions, or LAIs “…may be
preferable for patients who have difficulty swallowing pills or who are ambivalent about medications
and inconsistent in swallowing them.”27

o Other strategies mentioned in the guideline for improving patient ability to remember to
take their daily medication include behavior training, simplification of oral regimens/pill
burden, or use of watches/phone alarms, pillboxes, or family to assist with medication
reminders especially for patients with cognitive impairments.

LAI options can be discussed with patients if they have had an insufficient response to the oral
antipsychotic, especially since a patient’s adherence to oral medication may be over-estimated.27 LAIs
may also be considered for patients at risk of poor adherence, those with limited ability to grasp their
condition or benefits of consistent medication intake, or for those with co-occurring substance use
disorder.27

Guidance from the Florida Center for Behavioral Health Improvement and Solutions group supports
having LAI SGA therapy as an option for initial maintenance treatment of schizophrenia “…after the
patient has been stabilized or after obtaining sufficient evidence for efficacy and tolerability…”; and for
patients non-adherent or refractory or oral therapy.24 Additional special populations for which first-line
use of LAIs is especially recommended include patients with poor insight or cognition, homelessness,
poor support system, dangerous behavior, or suicidality. Of the SGA LAIs, olanzapine pamoate is listed
as a second-line LAI option due to its risk for post-injection delirium/sedation syndrome. Nonetheless,
the choice of product is ultimately patient-specific considering the patient’s response to oral therapy
and tolerability patterns, contraindications, and preferences.24

Comparative Evidence (Oral vs. LAI therapy): The APA guideline summarizes comparative evidence
between antipsychotic LAIs and oral agents as follows:

“Although meta-analyses of head-to-head RCTs comparing LAI with oral antipsychotics (McDonagh
et al. 2017) and other meta-analyses of RCTs (Kishi et al. 2016a, 2016b; Kishimoto et al. 2014;
Ostuzzi et al. 2017) do not show evidence of benefit from LAIs relative to oral antipsychotic
medications, observational data from nationwide registry databases (Taipale et al. 2018a, 2018b;
Tiihonen et al. 2011, 2017), cohort studies (Kishimoto et al. 2018), and “mirror image” studies
(Kishimoto et al. 2013) suggest that use of LAI antipsychotic agents as compared with oral
antipsychotic medications is associated with a decreased risk of mortality, reduced risk of hospital-
ization, and decreased rates of study discontinuation (including discontinuation due to inefficacy).”27

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 • In the systematic review by Ostuzzi et al (2017) which captured RCTs that specifically
compared the LAI to the same oral active ingredient, meta-analysis suggested no significant
advantage in response rate or risk of relapse with the LAI form of aripiprazole, risperidone, or
olanzapine versus the oral counterpart; dropouts due adverse events, extrapyramidal
symptoms, and weight gain were also similar between the LAI and oral formulation.32 Yet,
some RCTs, individually, may have shown significant differences, for example Subotnick et al
found that Risperdal Consta outperformed oral risperidone for relapse prevention, psychotic
symptom control, and adherence in patients after a recent first episode of schizophrenia
(open-label study).33 We are also aware of a more recent open-label RCT finding better
negative symptom control after 6 months with the once monthly paliperidone versus oral
extended-release paliperidone in patients.34

For Bipolar I Disorder

If psychosocial strategies such as psychoeducation are ineffective in addressing/improving non-

adherence to oral antipsychotic therapy, then LAI medication should be offered according to the
CANMET 2018 bipolar treatment guideline.9 A guideline by the British Association for
Psychopharmacology advises that LAIs should be provided to prevent mania recurrence in patients with
erratic adherence or for those who prefer LAI therapy. Authors note that the use of other options than
those approved for bipolar disorder “…will represent extrapolation from oral efficacy or class effect of
dopamine antagonists/partial agonists and clinical experience…”35 Guidance from the Florida Center for
Behavioral Health Improvement and Solutions group supports continuing the regimen that stabilizes the
patient as maintenance therapy. LAI aripiprazole and LAI risperidone are among a list of agents that can
be considered first-line for initial maintenance therapy (without specifying the exact product).36

Maintenance treatment with risperidone LAI (every 2 weeks) as monotherapy or adjunctive therapy (to
lithium or valproate), and aripiprazole LAI (once-monthly) as monotherapy have demonstrated
effectiveness in prevention of mood episodes and mania in bipolar I disease. These LAI agents, however,
have unclear efficacy for prevention of depressive episodes in bipolar disorder.9

Pediatric Use
Labeling for LAI antipsychotics describes that their safety and efficacy are unestablished in the pediatric
population. Furthermore, Invega Trinza labeling specifically recommends against its use in the pediatric
population due to a higher potential for adverse events in pediatric patients. In studies with oral
paliperidone, higher incidences of dystonia, hyperkinesia, tremor, and parkinsonism were observed in
adolescents versus adults.6

Based on systematic reviews (SRs), there have been only open-label, non-controlled studies and case
reports for LAI antipsychotic use in youth.37,38 This low strength evidence suggests that LAI
antipsychotics may improve adherence and clinical outcomes for children with bipolar and
schizophrenia disorders. Side effects mentioned among these SRs included weight gain, tremor,
oculogyric crisis, hyperprolactinemia, sedation, and extrapyramidal symptoms.37,38

Guidance that we are aware of from the Florida Center for Behavioral Health Improvement and
Solutions group recommends that “Treatment with a long-acting depot antipsychotic agent should be

19 | P a g e
considered as clinically appropriate,” for pediatric patients with schizophrenia as a third-line option
when patients have failed at least 2 antipsychotics approved for use in adolescents.39 Of the LAIs
available, authors recommend against the use of Zyprexa Relprevv in pediatric patients since it has the
black box warning for post-injection delirium/sedation syndrome.39

B. ODT Products
B.1 ODT Product Description
The 4 available ODT antipsychotics are approved for schizophrenia (clozapine is for treatment resistant
disease), 3 are approved for bipolar I disorder (aripiprazole, olanzapine, and risperidone), 2 are
approved for irritability associated with autism (aripiprazole and risperidone), and aripiprazole is
additionally approved for Tourette’s disorder and for adjunctive therapy in major depressive disorder.

Table 6. ODT Second Generation Antipsychotics, Approved Indications 10-15,40

Aripiprazole ODT, Generic 10 and 15 mg
Approved for:
• Schizophrenia (≥13 years)
• Acute treatment of manic/mixed episodes in Bipolar I disorder (≥10 years)
• Adjunctive therapy, in Major Depressive Disorder (adults)
• Irritability, in Autistic disorder (6-17 years)
• Tourette's disorder (6-18 years)
Clozapine ODT, Generic 12.5, 25, 50, 100, 150, and 200 mg
• Treatment-resistant schizophrenia (adults)
• Suicidal behavior associated with schizophrenia or schizoaffective disorder (adults)
Olanzapine ODT, Brand (Zyprexa Zydis) and Generic available: 5, 10, 15, and 20 mg
• Bipolar I mania/mixed episode, acute and maintenance treatment (age ≥ 13 years)
• Schizophrenia (age ≥ 13 years
Risperidone ODT, Generic 0.5, 1, 2, 3, and 4 mg
• Schizophrenia (age ≥ 13 years)
• Irritability associated with autism (age 5-17 years)
• Acute treatment of manic/mixed episodes in Bipolar I disorder(age ≥ 10 years)

Once placed on the tongue, ODT dosage forms dissolve rapidly, beginning within seconds and usually
completely dissolved within one minute.41-43 The dissolved medication can then be swallowed with or
without liquid.13,15 This formulation may be more convent for patients without a beverage easily
accessible at the time of their dosage compared to a conventional tablet. The SGA ODT formulations are
bioequivalent (taking into account Cmax and AUC ratios) to their conventional tablet counterpart.44
There is insufficient evidence to conclude that the time to maximum concentration (Tmax) for the ODTs
significantly differs from the conventional table form (CTF); instead, evidence mostly supports a similar
Tmax.43,45-47 While a couple pharmacokinetic studies have suggested earlier appearance of drug plasma
levels with the ODT compared to the CTF, whether this results in significant differences in clinical
outcomes has not been established. Nonetheless, there may be perception among clinicians based on
their observations treating patients that a slightly earlier therapeutic onset is possible with ODT
formulations.48

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Three of these ODT drug moieties are also available as oral solutions: aripiprazole (generic solution; non-
preferred on the PDL), clozapine (brand only available as Versacloz; non-preferred on the PDL), and
risperidone (generic solution; preferred agent on the PDL); olanzapine is unavailable as an oral solution.

Table 7. ODT Product Pharmacokinetic Information 10-15,40

Aripiprazole ODT
• ODT formulation has similar Cmax and AUC (ie, bioequivalent) to conventional aripiprazole
tablet44
o Inter-subject variability in Cmax and AUC ranged from 7.7% to 27.6% for the ODT
product in bioequivalence studies
• <1% of dose excreted in urine unchanged and <18% unchanged in feces; metabolism occurs
mainly through CYP 3A4 and 2D6 (see package insert for drug interaction related dose
adjustments); active parent molecule and active metabolite is dehydro-aripiprazole
• Tmax of 3-5 hours reported in the package insert
Other Tmax information reported in the literature
 Similar plasma concentration–time curves over 12 hours for Abilify ODT vs Abilify conventional
tablet following a 15 mg dose, and mean Tmax occurring around 5 hours for both formulations in
healthy middle-aged Koreans under fasting conditions.45
 No significant difference in Tmax among 167 healthy volunteers receiving 10 mg of Abilify ODT
vs. Abilify conventional tablet under fasting conditions.46
Clozapine ODT
• ODT formulation is bioequivalent to clozapine tablets based on steady state data
• Median Tmax of 2.5 or 4 hours under fasting and fed conditions, respectfully ; mean Tmax of 2
hours and 2.5 hours for the parent molecule and active metabolite (desmethylclozapine),
respectfully (at steady state with ODT tablet)49
• About 50% of dose excreted in urine and <30% in the feces; metabolism occurs mainly through
CYP 1A2, 3A4 and 2D6 (see package insert for drug interaction related dose adjustments)
• No comparative Tmax information for ODT vs. conventional tablet was found
Olanzapine ODT
• ODT olanzapine is bioequivalent to olanzapine conventional tablets
• Tmax: about 6 hours per package insert
• Metabolism occurs via 1A2 and 2D6 (minor) enzymes, and by flavin-containing monooxygenase;
about 57% and 30% of the dose was recovered in the urine (7% unchanged) and feces,
respectively.
Other Tmax information reported in the literature
 Median Tmax in hours for Zyprexa Zydis (olanzapine) 5mg in healthy Chinese volunteers (males
and females): 4.5 (range 2.0-7.5) under fasted condition and 4.5 (range 4.0-6.5) in fed condition
(no comparator arm).50
 Mean Tmax in hours for Zyprexa (from all male U.S. study, N=11): 3.47 (SD 1.93) for ODT and
4.37 (SD 1.57) for conventional tablet under fasting condition. Although authors note slightly
earlier appearance of drug in plasma via ODT form, the Tmax, AUC, and Cmax were not
statistically different.47 There may be differences in metabolism between males vs. females so
this data may not be generalizable to women (eg, estrogen inhibition of CYP1A2, or potentially
lower activity of the UGT enzyme due to smaller size of the liver and the kidneys in females).50

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 Table 7. ODT Product Pharmacokinetic Information 10-15,40
 A single conference abstract reported more rapid absorption with ODT and that more patients
with ODT have earlier measurable concentration compared to a conventional tablet (UK study in
59 healthy volunteers). Nonetheless, authors do not report the brand or generic
manufacturer/product used in the abstract, so it is unclear if their products used match those
available in the US.51
Risperidone ODT
• ODT is bioequivalent to risperidone tablets
• Tmax: about 1-2 hours43
• Highly metabolized in the liver mainly by CYP 2D6 (active metabolite 9-hydroxy-risperidone); CYP
1A1, 1A2, 2C9, 2C19, and 3A4 may also be minor pathways; 70% of dose excreted in the urine
and 14% in the feces
Other Tmax information reported in the literature
• Mean plasma concentration-time profiles and Tmax values of risperidone ODT and conventional
tablet were similar; Tmax for ODT was 1.33-1.49 hours for risperidone and 1.54-1.8 hours for the
active metabolite; and for the conventional tablet was 0.92-1.25 hours for risperidone and 1-1.4
hours for the active metabolite43
Abbreviations: BAP/NAPICU, British Association for Psychopharmacology and the National Association of
Psychiatric Intensive Care and Low Secure Units; ODT, orally disintegrating tablet; SD, standard deviation; Tmax,
time to maximum concentration

Comparative Effectiveness (ODT vs. Conventional Tablet): Head-to-head studies comparing the ODT
versus the conventional tablet have mainly been conducted with olanzapine. A 2012 review of these
studies reports similar efficacy for schizophrenia symptom improvement or maintenance of
improvement with ODT olanzapine versus conventional tablet based on several comparative studies (2
RCTs, 4 prospective cohort studies, and 1 retrospective study).48 RCT studies in patients with bipolar
disorder also show similar improvements in symptoms.52,53 One RCT found significant differences in
compliance favoring the ODT;53 the second RCT found compliance, as measured by tablet count, was
above 98% with both formulations.54 Some of the observational evidence shows that the ODT form is
preferentially prescribed to more difficult-to-treat, non-adherent patients.48 A 2017 observational study
in previously non-adherent patients with bipolar disorder or schizophrenia, described greater reductions
in relapse and hospitalization with ODT olanzapine versus olanzapine conventional tablet.55 Robust RCTs
have not reproduce differences in weight gain between the two olanzapine formulations as initially
found in some observational studies.48,53,54,56

B.2. Place in Therapy for ODT Products

Adherence or Compliance (eg, reduce ability to “cheek” medication, or as an alternative for

patients who have swallowing difficulties)

 Oral disintegrating tables and oral solutions may be considered for patients with trouble
swallowing pills or for patients who will not consistently swallow pills, per the American
Psychiatric Association guideline on the treatment of schizophrenia.27

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  Authors of the 2018 CANMAT bipolar treatment guideline note that “If a patient indicates
willingness to take oral treatment but there is a suspicion that the patient might “cheek” the
medication, then either orally dispersing tablets (ODT), those that rapidly melt, oral liquid, or
oral inhalation forms should be considered.”9
 As noted in the 2020 American Academy of Pediatrics guideline regarding autism,
developmental delays in children may include oral-motor issues in which case the child may be
unwilling or unable to swallow certain foods/textures/medications; swallowing discomfort can
also be a factor.57
 From the 2016 American Psychiatric Association guideline for the treatment of agitation or
psychosis in patients with dementia: In patients experiencing difficulty swallowing pills, it is
preferable to provide an ODT or oral concentrate formulation, especially since swallowing
difficulties can lead to poor adherence.58
 Improved outcomes in previously non-adherent patients may be related to better adherence
and acceptability of the ODT product due to the ease of use (liquid not required) and overall
preference for ODT vs. swallowing a conventional tablet.
• OLN Retrospective Studies
o Novik et al (2017) post-hoc analysis: Data from a retrospective, open-label study
suggested improved outcomes at 1 year (lower odds of relapse or hospitalization)
when previously-treated, non-adherent patients with schizophrenia or bipolar
disorder were switched to ODT olanzapine versus olanzapine conventional tablet.55
o Kinon et al (2003) performed a non-controlled, open-label study in patients with
schizophrenia and prior non-adherence to antipsychotics. After 6 weeks of ODT
olanzapine treatment, significant improvements from baseline were observed in
schizophrenia symptoms (per Positive and Negative Syndrome Scale), patient
adherence and attitudes, and reduced nursing care burden.59
 For the treatment of agitation associated with psychiatric disorders, a short-acting oral SGA such
as an ODT may be selected in place of an SGA IM short-acting formulation (IM aripiprazole, IM
olanzapine, and IM ziprasidone have approval for agitation associated with schizophrenia or
bipolar I mania). The IM aripiprazole product is no longer available for business reasons and
there are no IM short-acting products for clozapine or risperidone.
Further Information Regarding Rapid Mitigation of Acute Agitation/Aggression Associated with
Various Psychiatric Disorders

Pharmacologic treatment of agitation can prevent a violent situation for the care-taker (eg, healthcare
staff [during admissions] or behavior-intervention team of a treatment facility).60 The aim is to use a
dosage that will calm the patient, thereby reducing the risk of harm to self and others, without
necessarily causing the patient to fall asleep.27,60 Oral antipsychotic options may be selected, based on
medical history and underlying etiology of agitation, to avoid escalation to violence and the need for
parenteral medication and physical restraint. Oral antipsychotics are preferred in guidelines before
resorting to an IM antipsychotic if the patient is cooperative.40,60 Patients may be more accepting of an
ODT vs. conventional tablet and the ODT can help circumvent “cheeking” and improve adherence.9,40
Additionally, this formulation should be offered for patients with swallowing difficulties, if
appropriate.40,58

23 | P a g e
Appendix B summarizes the SGA drug moieties, along with other pharmacologic agents, that are
recommended among the following guidelines for the management of agitation/aggression:

• Consensus recommendations from the American Association for Emergency Psychiatry

regarding pharmacotherapy for the management of agitation (2012)60
• Joint BAP/NAPICU guidelines for the management of acute disturbance (2018)40
• NICE guideline regarding short-term management of violence and aggression in mental health,
health, and community settings (2015)61
• The American Psychiatric Association guideline on the use of antipsychotics for agitation or
psychosis in patients with a neurocognitive disorder (eg, dementia) (2016)58
• CANMAT guideline for the treatment of bipolar disorder (2018)9
• Canadian guideline for the treatment of aggressive and disruptive behaviors in youth (2015)62

The American Psychiatric Association described that “Although as-needed or emergency administration
of antipsychotic medication may, at times, be useful in individuals with acute agitation, it can also
reduce tolerability and contribute to a perception that premature dose increases are needed.”27 The
British Association for Psychopharmacology guideline recommends that as-needed (PRN) use of
antipsychotics for an acute psychotic episode should be regularly reviewed for appropriateness,
frequency of use, cumulative dosages administered, and therapeutic benefits or side effects.28 The NICE
guideline advises that PRN use for acute aggression should include the rationale and circumstances for
when PRN medication will be used, a plan to not exceed maximum daily dose in combination with the
patient’s other medication, and the plan should be discussed with the patient if possible.61

24 | P a g e
Prior Authorization (PA) Considerations

Potential criteria for initiation of LAIs

May consider requiring the prescriber’s attestation or documentation of the patient’s prior
tolerance to the corresponding active ingredient (or risperidone for Invega Sustenna) prior to
initiation of the LAI.
o Product labels (with exception of Invega Trinza) state that patients should demonstrate
tolerability to the oral product prior to initiating therapy with the LAI. While the term
“prior to” can be interpreted in various ways, it should be considered that tolerance could
be temporally related to patient conditions at the time tested (ie, health status, other
potential impacting factors such as concomitant medications) and changes in such factors
may influence tolerability.
o It is also possible that the patient has tolerated a different LAI product with the same
active ingredient prior to initiating a new LAI, thus, tolerability may be established but not
necessarily via recent use of oral therapy.
o In a survey of US experts on LAI antipsychotic therapy, prescribers “…appeared to prefer
shorter intervals (4–14 days) of oral medication before initiating treatment with an LAI of
the same molecule…”22

For Invega Trinza, may consider requiring at least 4 consecutive months of Invega Sustenna therapy
immediately preceding initiation of the Trinza product, with the last two Sustenna doses being
stable (ie, the same dosage) and in the range of 78 – 234 mg/month. Conversion for Invega
Sustenna 39 mg/month is not provided/accommodated with the Trinza strengths studied.
Additional criteria for the non-preferred agent Risperdal Consta

May consider additional PA requirement for prior trial/failure of Invega Sustenna or Perseris, or
provide clinical rationale (eg, bipolar I indication) for the use of Risperdal Consta instead of these
PDL-preferred agents that can also be used for patients with schizophrenia who demonstrate
tolerability to oral risperidone.

Product dispensing and administration

Consider maintaining the current mechanism, requiring that SGA LAI antipsychotics be dispensed to
the prescriber or their representative, since this helps ensure that LAI SGAs are administered by a
healthcare provider (as directed per FDA labeling), and that the prescriber is aware of the patient’s
adherence patterns and antipsychotic exposure.

Other considerations: concomitant oral/LAI antipsychotic use

Retrospective pharmacist review may be considered to assess prescriber rationale for ongoing
overlapping oral antipsychotic use with an LAI antipsychotic, especially if provided by a different
prescriber or if the oral agent is a refill of a prescription written before the initiation of the LAI. A
retrospective review/peer-to-peer intervention approach (vs. PA) can avoid delaying coverage for
oral supplementation to address psychotic exacerbations or for other scenarios requiring overlap
(eg, LAI initiation phase or missed/late doses).

25 | P a g e
 o This could prevent accidental or intentional refilling of an oral antipsychotic, without the
provider’s direction, as the patient may have remaining refills of their previous oral product
at the pharmacy (+/- automatic refill service).
o This may catch oral prescriptions provided by a different prescriber unaware of the
patient’s use of an LAI antipsychotic and improve coordination of providers.

There is an existing PA restriction applied for the use of multiple antipsychotics in patients under
20 years old according to the Medicaid PDL. It is unclear if this restriction prevents certain patients
indicated for LAI therapy from receiving oral-antipsychotic supplementation during the LAI
initiation phase, for a missed/late LAI dose, or to address symptom exacerbation.

 Refer to page 10 regarding the management of breakthrough psychosis

Potential PA criteria for PDL non-preferred ODT products

May require medical necessity rationale for prescribing of ODT formulations (eg, trouble swallowing
pills or will not consistently swallow pills, contraindication to preferred product, or indication not
covered by the PDL preferred ODT [eg, Tourette’s disorder, autism-related irritability]).

26 | P a g e
Summary
LAI Antipsychotics: Poor or indiscernible adherence patterns with oral antipsychotic therapy, and
patient preference are among the reasons that patients may be transitioned to an LAI antipsychotic.
Because LAI therapy is administered directly by the healthcare provider, adherence patterns are readily
apparent. Additionally, LAIs have inherently less overdose potential versus providing a take-home supply
of oral medication for self-administration—a reason an LAI may be preferred for certain patients.

A 2020 American Psychiatric Association guideline for the treatment of schizophrenia recommends for
patients to receive an LAI antipsychotic if they prefer such formulation or if the patient has a history of
poor or uncertain adherence.27 Guidance from the Florida Center for Behavioral Health Improvement
and Solutions group supports having LAI SGA therapy as an initial option, among other agents, for
maintenance treatment of schizophrenia or bipolar I disorder; and for patients with schizophrenia non-
adherent or refractory to oral therapy.24

Prior to initiation of LAI SGAs, patients should have tolerated the corresponding oral antipsychotic, while
Invega Trinza should be preceded by at least 4 months of treatment with Invega Sustenna. When
transitioning from oral therapy, supplementation with an oral antipsychotic is required during the
initiation phase of Abilify Maintena, Aristada, and Risperdal Consta; and in the event of a late dose of
these products. Oral supplementation may also be needed to address breakthrough symptoms and/or
while optimizing the antipsychotic regimen; or when there are CYP-inducer related drug interactions
with some products (see page 9/10 for details).

Following the administration of Zyprexa Relprevv, the patient must be observed by the healthcare
provider for 3 hours post-injection due to the risk of severe sedation (ie, post-injection
delirium/sedation syndrome), a black box warning for this product. Even though, this severe reaction
occurs infrequently, in <0.1% of injections and in about 2% of patients during clinical trials,4 the
observation requirement may impact the practicality of using this medication for some providers,
patients, or practice settings.

ODT Antipsychotics: Four orally-disintegrating SGAs are available and have the same indications as their
respective conventional-tablet counterpart. ODT products (along with oral solutions and potentially
LAIs) are options for patients who have difficulty swallowing whole tablets. ODTs can also help address
compliance/adherence issues. In treatment guidelines for schizophrenia and bipolar disorder, authors
note that ODT antipsychotic formulations should be considered for patients who will not consistently
swallow pills or for patients who may “cheek” a conventional tablet.9,27

For the treatment of acute aggression, oral antipsychotics are preferred over resorting to an IM
antipsychotic formulation, if the patient will cooperate with taking an oral product. Patient involvement
in the choice of antipsychotic formulation is advocated in guidelines for the treatment of aggression.60,61
While preference is not necessarily stated specifically for ODTs over the conventional tablet form, in
guidelines for treating aggression/agitation, authors note that an ODT can help with compliance during
the treatment of acute agitation/aggression due to rapid dissolution once in the mouth.40,58

27 | P a g e
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Appendix A: Literature Searches
Database(s): Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and
Daily 1946 to November 25, 2020

# Searches Results

meta-analysis/ or (metaanaly$ or meta-analy$).ti,ab,kw,kf. or "Systematic Review"/ or ((systematic* adj3

1 349444
review*) or (systematic* adj2 search*) or cochrane$).ti,ab,kw,kf. or (cochrane$ or systematic review?).jw.

2 (MEDLINE or systematic review).tw. or meta analysis.pt. 296398

3 1 or 2 382714

(("long-acting injectable*" or depot* or LAI*) and (antipsychotic* or aripiprazole or olanzapine or risperidone or

4 1683
paliperidone)).ti,ab.

5 3 and 4 168

6 limit 5 to yr="2011 -Current" 116

Database(s): Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and
Daily 1946 to December 11, 2020

# Searches Results

meta-analysis/ or (metaanaly$ or meta-analy$).ti,ab,kw,kf. or "Systematic Review"/ or ((systematic* adj3

1 352380
review*) or (systematic* adj2 search*) or cochrane$).ti,ab,kw,kf. or (cochrane$ or systematic review?).jw.

2 (MEDLINE or systematic review).tw. or meta analysis.pt. 298686

((disinteg* or ODT* or dissol*) and (antipsychotic* or olanzapine or aripiprazole or risperidone or

3 237
clozapine)).ti,ab.

4 1 or 2 385810

5 3 and 4 5

Epistemonikos.org
ODT SR Search, December 1st 2020

 Title/Abstract: (ODT OR disint* OR dissol*) AND (antipsychotic* or olanzapine or aripiprazole or

risperidone or clozapine)

LAI-A SR Search, December 8th 2020

 Title/Abstract ("long acting injectable" AND antipsychotic*) OR ("LAI antipsychotic*") OR (depot*

AND antipsychotic*)

32 | P a g e
Appendix B: Treatment Guidelines Addressing Rapid Mitigation of Acute
Agitation/Aggression

2012 Consensus Recommendations from the American Association for Emergency Psychiatry60

Best-practice pharmacologic approaches for agitation in the emergency department include patient
involvement, if possible, in the choice of intervention. The 3 classes of medications used for agitation
management include benzodiazepines, FGAs, and SGAs.60 Medication selection depends on the patient’s
medical history and underlying etiology of agitation. Formulations used are immediate-release oral (eg,
tablets and ODTs) or parenteral (IM and rarely IV) preparations. SGAs with the most supportive evidence
for agitation (eg, olanzapine, risperidone, or ziprasidone) are recommended over FGAs, with the
exception being haloperidol as the first-line agent for agitation associated with CNS depressant
intoxication. When a patient will not cooperate with an oral intervention, then an IM formulation is then
used. If agitation is accompanied with delirium or a result of a suspected medical condition aside from
bipolar disorder or schizophrenia (eg, hypoglycemia, electrolyte imbalance, hypoxia) an attempt to treat
the underlying condition should be made prior to administration of an antipsychotic.60

Table 1. Recommended Treatments for Agitation per 2012 Consensus of the American Association
for Emergency Psychiatry Workgroup60

For agitation associated with psychosis in a patient with known psychiatric disorder OR for agitation
associated with delirium (un-accompanied by alcohol or benzodiazepine withdrawal), recommended
options include the following in order of preference:60

o Oral SGAs: risperidone 2 mg (strongest evidence for safety/efficacy) or

olanzapine 5-10mg
o Oral haloperidol
o IM olanzapine 10mg or IM ziprasidone 10-20 mg (both require reconstitution)
o Parenteral haloperidol: IM, or IV (IV usually only for agitation with delirium)
 If initial dose of antipsychotic is insufficient, addition of a benzodiazepine should be
employed as opposed to an additional dose of the same or alternative antipsychotic.
 Quetiapine is typically avoided when patients may be volume depleted since has a high risk
of orthostatic hypotension.

For agitation due to CNS depressant intoxication: oral or IM haloperidol (2-10mg) is recommended since
it has the most supportive evidence60

 Haloperidol has minimal anticholinergic activity and vital sign effects relative to phenothiazine
FGAs (eg, chlorpromazine), so is the preferred FGA.60
 Situations where haloperidol is avoided are in patients vulnerable for QTc prolongation (eg,
preexisting long QTc, predisposing conditions such as cardiac abnormalities, electrolyte
imbalance, or hypothyroidism).60 Haloperidol is typically administered in combination with
lorazepam, promethazine, or diphenhydramine since studies have shown reduced incidence of
extrapyramidal side effects with such combinations.60

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 Table 1. Recommended Treatments for Agitation per 2012 Consensus of the American Association
for Emergency Psychiatry Workgroup60
For agitation during stimulant intoxication, ethanol withdrawal, or when the etiology of is
undetermined: Benzodiazepines (BZDs) are preferred and have a long track record of efficacy for
agitation.60
 BZDs are used cautiously or avoided in the presence of underlying respiratory conditions or in
combination with other CNS depressants. When psychosis is present as a result of long-term
stimulant abuse of amphetamines, an antipsychotic “…is often useful in addition to, or in place
of, a benzodiazepine.”60 Benzodiazepines are also generally avoided during delirium since they
can exacerbate the delirium.60

2018 Joint BAP/NAPICU Guidelines for the Management of Acute Disturbance40

This guideline defines acute disturbance as “…an acute mental state associated with an underlying
mental and/or physical disorder in the form of: (i) agitation and distress, which is excessive verbal or
motor activity that may or may not lead to aggression or violence; or (ii) actual aggression or violence
entailing harm, hurt or injury to another person, or damage to property regardless of whether it is
verbally or behaviourally expressed, physical harm is sustained, or the intention is clear.”40

Prior to the use of injectables for acute disturbance de-escalation, the 2018 Joint BAP/NAPICU guideline
recommends the following agents in order of strength of recommendation (but not in necessarily in
preference of one over another):

• Oral-inhaled loxapine (contraindicated in patients with asthma or chronic obstructive pulmonary

disease) (recommendation strength, A)
• Oral formulations of aripiprazole, olanzapine and risperidone (recommendation strength, A)
• Oral haloperidol (recommendation strength, C)
• Oral quetiapine (recommendation strength, C)
• Buccal midazolam (recommendation strength, C)
• Oral lorazepam and oral promethazine may be effective

Authors note the common practice of PRN (pro re nata, as required) medications for patients admitted
to acute psychiatric wards for the management of acute disturbance; yet, there are no randomized
controlled trials comparing this approach versus others, nor are there robust studies for a second PRN
antipsychotic added to a maintenance antipsychotic.40

NICE 2015 Guideline: Violence and Aggression: Short-Term Management in Mental Health, Health and
Community Settings61

• When pharmaceutical intervention is necessary for the management of violence/aggression, an

oral product should be used if appropriate and reasonable; otherwise, an IM product is to be
used when violent behavior requires urgent pharmacological treatment or when the oral route
is not practical or has been insufficient. Intervention using oral medication is aimed at
preventing escalation of violence/aggression and the need for IM rapid tranquilization. This also

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 encompasses “…p.r.n. medication given earlier than usual because nursing staff have detected
signs of impending violence.”61
• In children and young persons, the pharmaceutical agent recommended for rapid IM
tranquilization is IM lorazepam
• Health and social-care provider organizations should “…ensure the safety of staff …”61
• In-patient psychiatric unit: “A multidisciplinary team that includes a psychiatrist and a specialist
pharmacist should develop and document an individualised pharmacological strategy for using
routine and p.r.n. medication to calm, relax, tranquillise or sedate service users who are at risk
of violence and aggression as soon as possible after admission to an inpatient psychiatric unit.”61
This should include the rationale and circumstances for when p.r.n medication will be used, a
plan to not exceed maximum daily dose in combination with the patient’s other medication, and
the plan should be discussed with the patient if possible. A senior doctor should review the
patient’s medication regimen/plans at least once a day if rapid tranquillisation with IM agents is
being used.61

The American Psychiatric Association Guideline for Antipsychotic Use to Treat Agitation/Psychosis in
Patients With Dementia or a Major Neurocognitive Disorder58

The use of nonemergency antipsychotic medication is recommended only for agitation or psychosis
when symptoms are severe (ie, posing danger and/or causing significant distress) (1B) 2, and if the
risk/benefit assessment favors use of an antipsychotic.58 The selected agent should be started at a low
dose and gradually titrated to the minimum effective dose. If a clinically significant response is not
evident after a 4-week trial of an adequate dosage, the antipsychotic should be tapered off. Patients
experiencing difficulty swallowing pills should have access to rapidly dissolving tablet or oral concentrate
formulation, since swallowing difficulties can lead to poor adherence.58

 Best evidence for SGA therapy for agitation or psychosis is mainly from studies with
risperidone (moderate strength of evidence and small effect size for agitation; low strength of
evidence and a very small effect size for psychosis).
 Evidence for SGAs in the management of overall behavioral/psychological is strongest with
aripiprazole but only a small effect size is expected (moderate strength of evidence)
• In the absence of delirium, haloperidol should be avoided as a first-line agent.
• Long-acting injectable antipsychotic medication should not be utilized unless it is
otherwise indicated for a co-occurring chronic psychotic disorder.

CANMAT 2018 Bipolar Guideline9

Agitation is a common symptom during manic episodes especially in patients with mixed bipolar
features.9 Agitation is defined in the DSM-5 as “excessive motor activity associated with a feeling of
inner tension,” and can become severe with the patient acting out in uncooperative, threatening, or
aggressive behavior; but akathisia should be ruled out since it can appear as agitation.9

CANMET advises first considering rapid-acting oral antimanic medications for patients with bipolar I
mania/agitation prior to injectable therapy, even though the highest level of evidence with any oral

2
1B, translates to confidence that the benefits of the intervention clearly outweigh harm

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agent is level 3 (and is level 2 for IM forms).9 Authors further note that “In this context… the absence of
evidence does not constitute lack of efficacy.”9 Regarding ODTs, if the patient seems willing to use an
oral medication, but “…there is a suspicion that the patient might “cheek” the medication, then either
orally dispersing tablets (ODT), those that rapidly melt, oral liquid, or oral inhalation forms should be
considered.”9

Use of Antipsychotics in Youth for Disruptive and Aggressive Behavioral Disorders

Maladaptive aggression, often impulsive, is associated with several pediatric conditions including
oppositional defiant disorder (ODD), conduct disorder (CD), ADHD, disruptive mood dysregulation
disorder (DMDD) and bipolar disorder.63 In the DSM-5, ODD and CD are categorized as forms of
disruptive, impulse-control, and conduct disorders whereas DMDD is listed as a type of depressive
disorder, and ADHD as a neurodevelopmental disorder;64 yet there can be significant overlap in the
behaviors of these conditions.63 Aside from first-line psychosocial treatment, initial pharmacotherapy
should aim to treat underlying comorbidities (eg, ADHD, anxiety, etc.).62,65 Antipsychotics may be
considered for severe, potentially harmful aggression that persists despite a trial of medication for the
underlying disorder associated with aggression (grade A evidence, very strong recommendation per
2012 CERT guideline).63 Key points from the 2015 Canadian guideline for the treatment of aggressive
and disruptive behaviors in youth include the following:62
1. Medications may be considered when psychosocial therapies are insufficient
2. ADHD medications should be used first to treat disruptive or aggressive behaviors in children
with ADHD (regardless of whether ODD or CD has been diagnosed)
3. For patients with diagnosed ODD or CD, with or without ADHD, risperidone can be considered
when response to psychosocial therapy (and stimulants for ADHD) have been insufficient, based
on at least high-quality evidence of improvement in disruptive/aggressive behavior; for those
with a low intelligence quotient (IQ), the quality of evidence is moderate. There is very low
quality evidence for haloperidol and quetiapine.
4. Risk of antipsychotic-related adverse events (eg, movement and metabolic disorders) may
outweigh the benefits

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Appendix C

Table 1. Summary of Select Recent Clinical Practice Guidelines for Schizophrenia in Adults
Guideline Select Recommendations
Practice Guideline Evidence in guideline is based on the SR by McDonagh et al. 2017 that included some
for the Treatment patients with schizophreniform disorder, and schizoaffective disorder. In addition, the
of Patients with authors concluded that evidence for antipsychotic treatment is most applicable to “adults
Schizophrenia, 3rd (mean age 25 to 50 years), with mainly moderate-to-severe disease”
edition; American  Person-centered care, including pharmacologic and non-pharmacologic treatments (eg,
Psychiatric psychosocial interventions) are recommended.
Association, 202027 • Recommends use of antipsychotics for the treatment of schizophrenia.
• Consider clozapine for treatment-resistant schizophrenia (1B) or if there is substantially
high risk of suicide or aggressive behavior.
• Suggests LAI antipsychotic formulation if preferred by the patient, or with history of
nonadherence (2B)
• Recommends that patients with symptom improvement on an antipsychotic should
continue to be treated with an antipsychotic medication (1A)
• Lowering the antipsychotic dose or switching to a different antipsychotic is
recommended for management of antipsychotic-induced parkinsonism (2C; alternative:
anticholinergic agent), or akathisia (2C; alternatives: add benzodiazepine or beta-
blocker)
Evidence-based Treatment of First Schizophrenia Episode
Guidelines for the • Antipsychotic selection should be individualized based on side effect profile. Initial dose
Pharmacological should be low to minimize adverse effects. (D)
Treatment of • Antipsychotics are the first-line treatment. Doses at the lower end of the therapeutic
Schizophrenia; range are recommended. (B)
British Association • Efficacy of various antipsychotics for the first-episode are expected to be similar
for Pharmacology, (“though some agents [e.g., olanzapine, amisulpride, risperidone] might perform slightly
201928 better than others”). Selection should be primarily based on the potential adverse
effects. (S)
• Monitor efficacy using a comprehensive scale. Initial trial dose may be 2 weeks (for oral
therapy), and total trial length at up to max dose for about 6 weeks. (B)
• Target should be symptom remission. Response is defined as at least 25% reduction in
total symptom score or reduction by at least 1 point on the CGI (within 2 weeks), or 40-
50% reduction or reduction by at least 2 CGI points after about 6 weeks. (B)
Maintenance Treatment
• Treat patients in remission with the standard dose of an antipsychotic for at least 2 years
to reduce the risk of relapse. (B)
• Offer LAI, “given the evidence of a lower risk of relapse.” (B); an adequate trial of LAI is
considered 3 months
• Review whether medication should be continued after 2 years if remission maintained
and patient is without evidence of psychotic symptoms. (D)
o Use shared decision-making and consider benefits and risks. (S)
• Consider clozapine for treatment-refractory disease after 2+ antipsychotic trials (and
despite adherence and other treatments such as family interventions and CBT). (D)
Acute Psychosis
Antipsychotic

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Table 1. Summary of Select Recent Clinical Practice Guidelines for Schizophrenia in Adults
Guideline Select Recommendations
• Similar criteria to first-episode, but also consider patient preferences (S) and past
experience in terms of efficacy and side effects (S)
• “The requirement for PRN prescriptions for antipsychotic medication should be regularly
reviewed in relation to the clinical indications, frequency of administration, therapeutic
benefits and side effects, and cumulative dosage” (S)
Response Maintenance
• Continue antipsychotic within target dose range; individualize selection based on prior
treatment, side effects, medication adherence, and comorbidities (S)
• Before switching treatments, ensure the antipsychotic had an adequate trial (dose,
duration) (S)
• Avoid using an intermittent treatment approach (B); The ideal duration of treatment is
unclear; authors suggest assessing individualized risk: benefit of continuation
• Consider LAI to monitor adherence or per patient preference (B)
Treatment-Resistant Schizophrenia (TRS)
Treatment-resistance = failed response to 2+ adequate antipsychotic trials
• “Clozapine should be the first-choice treatment” for patients with TRS (A)
o An adequate trial should be clozapine alone at least 6 months (B); Consider
augmentation of clozapine only after a minimum of 3 months of clozapine at an
optimized dose (S)
• Consider high-doses or combinations of other antipsychotics only after exhausting other
treatment options including clozapine (B); Monitor patients on high-dose or combined
antipsychotic regimens closely and only continue after 3 months if benefits outweigh
risks (S)
Treatment of Comorbidities/Specific Symptoms
• Mania/hypomania: Select antipsychotic based on patient characteristics (D); there is
little evidence, though there is limited evidence to support using paliperidone; Consider
mood stabilizers if manic symptoms persistent after an adequate antipsychotic trial (D)
• Substance use disorders: Ensure antipsychotic optimization; clozapine may be
considered if symptoms persist (C)
• Persistent hostility or aggression: Consider a trial of clozapine (B)
Adherence
Adherence “is the most common cause of relapse and associated with increased difficulty or
delay in achieving remission”
• When possible, account for risk of side effects, and patient-specific factors for tolerability
concerns when selecting an antipsychotic (S)
• Choose a simple regimen (S), assess tolerability (S), and assess for adherence in a non-
judgmental way (S)
• Consider using more objective measures (e.g., pill counts, plasma levels) to assess
adherence if nonadherence has been associated with relapse (S)
• Consider an LAI if nonadherence is associated with relapse, if patient preferred, or if
“avoidance of non-adherence is a clinical priority (S)
o After the first-episode of psychosis, LAI may be considered if poor adherence to
oral medications occurs (B)
Recommendations about Antipsychotics during Pregnancy:
• No absolute evidence of safety, but “available evidence suggests [antipsychotics] are not
major teratogens” (B)
• Discontinuing antipsychotics during pregnancy is not recommended due risk of relapse
(C)

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Table 1. Summary of Select Recent Clinical Practice Guidelines for Schizophrenia in Adults
Guideline Select Recommendations
• Avoid starting olanzapine in women with risk factors for diabetes when planning a
pregnancy (S)
• May continue a LAI if initiated prior to pregnancy and there is a high risk of recurrence
(S), but avoid a new start of LAI during pregnancy due to poor flexibility (S)
• Do not breastfeed while taking clozapine (D)
Guidelines for Guideline reviewed and adapted recommendations from 8 guidelines from other
Pharmacotherapy organizations (NICE, SIGN, AACAP, EPA), all published between 2011 and 2016.
of Schizophrenia in
adults; CPA, 201766 Pharmacotherapy for Adults
First Schizophrenia Episode
• Antipsychotics are recommended (from NICE, strong)
• Use shared decision-making for selecting an antipsychotic, incorporating discussion of
possible side effects and efficacy (from NICE, strong)
o Considers all antipsychotics to have similar efficacy; selection often based on side
effect profile
• During acute treatment, consider (from SIGN, grade D):
o If tolerated, continue initial antipsychotic for at least 2 weeks
o Assess response to initial response; if poor response, consider adherence and
substance use
o Consider changing the antipsychotic if no response by 4 weeks
o Reassess partial response after 8 weeks
Also consider formulation, “earlier use [of long-acting injections (LAIs)] in the course of
treatment has been advocated…discussion regarding their use should not be confined to only
those for whom nonadherence is a concern”
• Maintenance treatment (after controlling positive symptoms) should last at least 18
months (from SIGN, grade D)
Acute Exacerbation
• Increase dose /change antipsychotic; if tolerated continue at least 4 weeks; reassess
partial response after 8 weeks (from SIGN, grade D)
o LAI may be helpful for nonadherence
Maintenance Treatment
• Offer maintenance after acute treatment with an antipsychotic at a low to moderate
dose (from SIGN, grade B)
• Duration of maintenance after control of positive symptoms acutely, should be for at
least 2 years and maybe for 5 years or longer (from SIGN, grade A)
• Patients should be allowed either an oral or LAI (from SIGN, good practice)
Treatment of Treatment-Resistant Schizophrenia (TRS)
• Offer clozapine (from SIGN, grade A)
• Consider clozapine after non-response to 2+ antipsychotics (from SIGN, grade B)
o Definition of non-response varies; sometimes response has been defined as at least
20% decrease in one of the symptom domains as measured by a scale
o Resistance to antipsychotic treatment = “persistence of 2 or more positive
symptoms with at least a moderate level of severity, or a single positive symptom
with severe or greater severity, following 2 or more adequate trials with different
antipsychotic drugs”
o Adequacy of treatment (also include assessment of adherence including
antipsychotic plasma level if applicable):
 Oral: at least 6 weeks at middle or higher dose of therapeutic range
 LAI: at least 6 weeks at steady state

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Table 1. Summary of Select Recent Clinical Practice Guidelines for Schizophrenia in Adults
Guideline Select Recommendations
 Clozapine: at least 8 weeks, ideally 12 weeks at dose of 400 mg/d or greater
Treatment of Schizophrenia Resistant to Clozapine: Insufficient evidence to recommend a
specific treatment
Treatment of Specific Symptoms
• Aggression/hostility: Base treatment selection upon patient preference, past
antipsychotics, adverse effects, and medical history. Clozapine is indicated for those also
with TRS. (from SIGN, grade D)
 Notes that SRs suggest clozapine is superior for treatment of aggression
• Depressive symptoms
o Treat depression according to guidelines for treatment of depression, including use
of antidepressants (from SIGN, good practice)
Clinical Practice Guideline applies to schizophrenia spectrum disorders including schizophrenia,
Guidelines for the schizoaffective disorder, schizotypal disorder, schizophreniform disorder and “acute transient
management of psychotic disorder” with symptoms of schizophrenia. It does not include recommendations
schizophrenia and for childhood-onset of schizophrenia.
related disorders; Pre-psychotic/prodomal phase
RANZP, 201629 • Do not consider antipsychotics unless positive psychotic symptoms present for at least 1
week, patient is at risk (self-harm or aggression), or when symptoms continue despite
psychosocial treatments (EBR, III-1)
Treatment of first episode of “non-affective psychosis”
• Prefer SGA to FGA (due to better SE profile, especially EPS risk) [CBR]
o Select agent based on: patient preference, previous response, tolerability, and
potential long-term side effects (EBR, I)
o Flow diagram recommends these SGA first: oral amisulpride (not available in US),
aripiprazole, quetiapine, risperidone, ziprasidone
 If insufficient response (after 3 weeks), may consider olanzapine. “Where
possible, medicines with the least risk of weight gain should be selected”
 LAI may be considered for nonadherence
“There is little evidence that the SGAs are more effective than the FGAs in the acute
treatment of positive symptoms. However, there is some evidence than oral SGAs are more
effective than oral FGAs in relapse prevention”
• Avoid use of >1 antipsychotic “unless it has been clearly demonstrated that the person’s
symptoms are resistant to monotherapy” (EBR, II)
• Consider clozapine early if interventions not effective (EBR, I)
• Recommends lifestyle interventions for weight gain prevention (EBR, II), and considering
metformin for preventing weight gain if the SGA is at risk for weight gain “when these
risks cannot be adequately managed by switching medication” or by lifestyle (EBR, II)
• Duration: recommended to continue for minimum of 2-5 years (EBR, II)
Maintenance treatment
• Usually continue treatment with same antipsychotic with response during acute phase (if
benefits > risks, including side effects)
• If planning for LAI, select an oral option appropriate for transitioning (ie, same
antipsychotic)
• Stopping treatment: consider risks vs. benefits; patient should be well for at least 12
months before d/c
Treatment of acute relapse
• Consider alternative antipsychotic if no response after 2-3 weeks of treatment at the
recommended dose (+adherent) [EBR, II]

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Table 1. Summary of Select Recent Clinical Practice Guidelines for Schizophrenia in Adults
Guideline Select Recommendations
• Consider clozapine after 2+ antipsychotic trials (with at least one being a SGA) of
adequate dose (300-1000 chlorpromazine equivalents) and duration (6+ weeks) [EBR, I]
• LAI may be considered for poor adherence or patient preference (EBR, I)
• Address poor adherence, side effects, other comorbidities, social environment (EBR, II)
• If persistent symptoms after clozapine trial: adjunct to clozapine, or previous best
regimen + add adjunct (EBR, II)
Combination antipsychotics
• 2 antipsychotics “may be justifiable” if no response after monotherapy of 2 agents;
requires monitoring (EBR, II)
Considerations for comorbidities
• Consider alternative antipsychotic with possible benefit on mood symptoms if the
symptoms (ie, depression, anxiety) do not respond to psychological intervention (EBR, II)
• AD/anxiolytics may be added for persistent symptoms after optimizing antipsychotic
(EBR, II); consider agent without overlapping SE with the antipsychotic (EBR, IV)
Pregnancy
• Consider antipsychotics “associated with fewer fetal adverse effects in available registry
data (eg, olanzapine, quetiapine, risperidone)” (EBR, III-3)
Treatment of acute disturbances
Consider pharmacologic treatment if non-pharmacologic treatment unsuccessful
• Oral preferred to injectable treatment (CBR)
• Prefer SGA if an injectable is required (EBR, II)
o IM first line (when reusing oral meds, highly aroused, violent): olanzapine; IM
second line: droperidol
• Monitor and avoid overdosing when using as-needed medication (EBR, III-1)
Abbreviations: AACAP, American Academy of Child and Adolescent Psychiatry; AD, antidepressant; APA, American
Psychiatric Association; BAP, British Association of Psychopharmacology; CGI, clinical global impressions scale; d,
day; d/c, discontinuation; ECT, electroconvulsive therapy; EPS, extrapyramidal symptoms; European Psychiatric
Association (EPA); FGA, first generation antipsychotic; FGAs, first generation antipsychotics; IM, intramuscular; LOE,
levels of evidence; MA, meta-analysis; MS, mood stabilizer ; NICE, National Institute for Health and Care Excellence
(NICE); RANZCP, Royal Australian and New Zealand College of Psychiatrists; RCT, randomized controlled trial; ROB,
risk of bias; Scottish Intercollegiate Guidelines Network (SIGN); SE, side effect; SGA, second generation antipsychotic;
SGAs, second generation antipsychotics; SR, systematic review
APA Strength of Recommendation
1: Recommendation, benefits >harms; 2: suggestion, benefits > harms with some uncertainty
APA Strength of Evidence
A: high; B: moderate; C: low (all based on consistency of effect, directness of effect, precision, and ROB)
BAP Strength of Recommendation
A: direct level 1 evidence; B: direct level 2 or extrapolated from level 1 evidence; C: direct level 3 or extrapolated
from level 1 or 2 evidence; D: direct level 4 or extrapolated from level 1, 2, or 3 evidence; S: “standard of good
practice”
BAP Levels of Evidence for Causal Relationships:
Ia: MA of RCTs; 1b: 1+ RCT; IIa: 1+ non-randomized controlled study; IIb: 1+ other quasi-experimental study; III: other
non-experimental or descriptive study; IV: expert reports or opinion
RANZCP Strength of Recommendation
CBR = consensus-based recommendation, based on collective expert opinion
EBR = evidence-based recommendation when sufficient evidence
RANZCP LOE
I: SR of RCTs; II: RCT; IIII-1: pseudo-RCT; IIII-2: “comparative study with concurrent controls”; IIII-3: “comparative
study without concurrent controls”; IV: case-series or pre/post test

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Table 1. Summary of Select Recent Clinical Practice Guidelines for Schizophrenia in Adults
Guideline Select Recommendations
SIGN and EPA Grades of Recommendation (used in CPA)
A: 1+ high or low risk of bias SRMAs of RCTs or RCT with consistent results that applies to the population; B: SRs of
observational studies or high-quality case-control or cohort study with consistent results that applies to the
population or extrapolated evidence from studies under grade A;
C: case-control studies or cohort studies at a high risk of bias or extrapolated evidence from SRs of observational
studies or high-quality case-control or cohort study with consistent results that applies to the population
D: descriptive studies or expert opinion
Good practice: based on clinical experience

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