Prescribing Guideline
Choice of Long-Acting Injectable
Antipsychotic
PG23
Document control
Version
Date Issued
1.0
May 2014
2.0
July 2015
3.0
October 2018
Target audience/staff groups:
Ratifying Group:
Date ratified:
Implementation date:
Review date:
Document History
Version
Start
date
0.1
1.0
1.1
Apr15
2.0
End
date
Apr14
May14
Jul15
Author(s) Name / Job Title / Email:
Dr Keith Gilhooly, Consultant Psychiatrist, keith.gilhooly@nhs.net
Drug and Therapeutics Committee
October 2018
October 2018
October 2022
Author
KG
KS
KG
KS
AG
Jan 18
2.1
3.0
Jun 18
Oct 18
JBS
KG
JBS
History
New Guideline
Document ratified at DTC, signed off and added to Trust intranet
Update to reflect CCG commissioning decision. Information specific
to administration & monitoring of Olanzapine LAI (Appendix 3)
transferred to Clinical Protocol CP28.
Document ratified at DTC and signed off. Added to website and
prescribing app
Nov 2015: Document updated to reflect change in SPC for
aripiprazole LAI (deltoid administration now licenced indication).
Review date extended pending Audit in 2018
Added information on:- Xeplion a 3 monthly paliperidone injection, a
new Swedish study and the non-availability of Fluphenazine
Ratified at October DTC and signed off
PG23 - Choice of Long-Acting Injectable Antipsychotic
Approved by Drug and Therapeutics Committee: October 2018
Review Date: October 2022
Page 1 of 12
Choice of Long-Acting Injectable Antipsychotic
Key
LAI=long acting injection=Depot
FGA=First generation antipsychotic
SGA=Second generation antipsychotic SPC= Summary of Product Characteristics
The electronic version of this document offers hyperlinks in blue or red to navigate the document.
NOTE: All references to Maudsley Prescribing Guidelines within this guideline currently refer to the 11th
Edition and not the current (12th) edition.
Contents
Page
2
3
Contents
Introduction
Choice of LAI- Quick Reference Guide
1. Indications for using a second generation LAI (Table 1)
2. Procedure for prescribing SGA LAIs
3. Licencing
4. Non-orally compliant patients who have not demonstrated tolerability/response with oral SGA
5. Monitoring
6. Tolerability and adverse effects
4
6
7
8
11
12
Supporting Information.
7. Evidence to support recommendations given in table 1. Red letters in the quick reference guide relate to
these evidence boxes (hyperlinks in intranet version). Each evidence box has green numbers attached
signifying the points on Table 1 it has evidence for:
Box
A
Effectiveness of and Switching antipsychotics (5,14)
i
B
Weight gain/Diabetes/Dyslipidaemia, and Switching antipsychotic (9)
iii
C
Antipsychotics and Extra Pyramidal Side Effects (EPSEs)/Tardive Dyskinesia (T.D) risk (2, 6) iv
D
Other risk factors for tardive dyskinesia (2,6,7)
vii
E
Akathisia (2, 14)
viii
F
Bipolar disorder (4, 5)
viii
G
Negative/Cognitive symptoms/Anticholinergics (3, 5,12)
ix
H
Hyperprolactinaemia (8)
x
I
First episodes (10)
xi
J
Deltoid Injections (11)
xii
K
Very high Risk patients (14)
xii
L
Cardiac risks and Sudden Cardiac Death (SCD) (3, 6, 9)
xiii
M
Aripiprazole Pharmacodynamics
xx
Appendix 1
Special considerations in the old age group
xxi
Appendix2
Comparison of Risperidone LAIs vs Paliperidone monthly LAI (Xeplion) and Paliperidone 3 monthly
(Trevicta). For evidence quoted in links, paliperidone LAI can be considered generally equivalent
to risperidone LAI, but equivalent doses and other differences are detailed here.
References
PG23 - Choice of Long-Acting Injectable Antipsychotic
Approved by Drug and Therapeutics Committee: October 2018
Review Date: October 2022
Page 2 of 12
Introduction
Whether to use an LAI?
The focus of this guideline is aiding choices between FGA and SGA LAIs, not whether or not to use an
LAI in the first place. It is worth noting however a recent Swedish database study of 29 823 clients
(Tiihonen 2017) found that; “Clozapine and long-acting injectable antipsychotic medications were the
pharmacologic treatments with the highest rates of prevention of relapse in schizophrenia. The risk of
rehospitalization is about 20% to 30% lower during long-acting injectable treatments compared with
equivalent oral formulations.”
The most obvious scenario for use of an LAI is when there is lack of insight and overt non-compliance
which may need to be managed under the mental health act.
NICE (2014) Schizophrenia guidelines 178 recommend offering an LAI for those;
 -who would prefer such treatment after an acute episode
 -where avoiding covert non-adherence (either intentional or unintentional) to
 antipsychotic medication is a clinical priority within the treatment plan.
It is also important to take into account the service user's preferences and attitudes towards the mode of
administration (regular intramuscular injections) and organisational procedures (e.g. home visits and
location of clinics)
It is probably rare that a client will choose an LAI, and if they do there is likely to be a good reason such
as they can recognise that they struggle to consistently take their medication.
For further advice on when to use an LAI at all see Bazire (2014, pg. 155-162, 211). Maudsley guidelines (2012,
pg. 40-51) offers good LAI advice. See the final section of evidence box A pg. 16. for advantages of LAIs as a
whole.
Choice of LAI.
FGA and SGA LAI preparations are commissioned across Devon for the treatment of people with
schizophrenia. However, the commissioning statement for SGA LAIs (aripiprazole, olanzapine and
paliperidone) limits their use to people with schizophrenia who are non-adherent to antipsychotic
medication and where first generation antipsychotic depot injections are not clinically appropriate.
Due to finite resources across the Devon
healthcare community, it is recognised that is it
NOT currently possible to offer a fully NICE
compliant service (Fig 1) and SGA LAIs cannot
be routinely be offered as a treatment choice to
everyone (reflected in the commissioning
statement).
However, SGA LAIs may be considered and
offered as a treatment choice for individuals
identified in the clinical scenarios in Table 1
(below).
Fig 1:
The choice of antipsychotic medication should be made by
the service user and healthcare professional together, taking
into account the views of the carer if the service user agrees.
Provide information and discuss the likely benefits and
possible side effects of each drug, including:
 metabolic (including weight gain and diabetes)
 extrapyramidal (including akathisia, dyskinesia and
dystonia)
 cardiovascular (including prolonging the QT interval)
 hormonal (including increasing plasma prolactin)
 other (including unpleasant subjective experiences).
From Clinical guideline 178: Psychosis and schizophrenia in
adults: treatment and management (NICE, 2014)
The aim of this guideline is to aid clinicians in the choice of antipsychotic medication were a LAI
formulation is indicated, and to support the choice of medication where FGA LAI is not clinically
indicated.
This document offers clinical guidance to prescribers on the differences between the LAIs. It is not
PG23 - Choice of Long-Acting Injectable Antipsychotic
Approved by Drug and Therapeutics Committee: October 2018
Review Date: October 2022
Page 3 of 12
however an overall guide to the conditions mentioned here which can be obtained elsewhere.
Individuals, for whom a LAI treatment may be beneficial, often lack capacity to make decisions and
choices, or may refuse treatment altogether. In these circumstances the prescriber will need to select
and prescribe medication in the best interests of that person.
In order to ensure that SGA LAIs remain available as a treatment option for individuals in most need,
clinicians are requested to use this guideline and adhere to the Trust ‘Non-Approved Prescribing
procedure when considering the use of a SGA LAI (SOP MM26).
The first part of the quick reference guide (Table 1) sets out situations where the clinical indication for an
SGA LAI rather than an FGA LAI, is greatest, and therefore can be considered for a request (see
logistics, section 2). Each situation is backed up by evidence boxes in section 8. This does not mean an
SGA LAI must be prescribed in each situation, as other risk factors and licencing need to be taken into
account. If clinicians make a case for prescribing the SGA LAI’s for reasons not mentioned, they will still
be considered, but all requests are subject to approval first by the CD or ACD.
Treatment should be initiated in accordance with the products Summary of product characteristics
(SPC). An initial test dose (IM) may be required OR evidence to demonstrate previous tolerance to
medication (i.e. risperidone). For detailed advice on dosing and administration see the summary of
product characteristics (available at www.medicines.org.uk/emc/ ) and the BNF.
1. Choice of LAI- Quick Reference Guide (TABLE 1)
Table 1.-. The commissioning statement for SGA LAIs limits their use to people with schizophrenia who are nonadherent to antipsychotic medication and where first generation antipsychotic depot injections are not clinically
appropriate. The Trust Non-Approved Medicines procedure (SOP MM26) applies to all SGA LAIs.
Below is guidance on situations when it may be clinically appropriate to consider a SGA LAI, but multiple clinical
factors need to be taken into account (e.g. particularly cardiac) in each risk benefit prescribing decision.
See Box L for info on sudden cardiac death risk. Applications made for reasons not given here can still be submitted
for consideration.
Risk of EPSE/Tardive Dyskinesia (TD):
EPSEs (e.g. akathisia, parkinsonism, dystonia)/T.D, are the major
LAI
concern when prescribing FGA LAI’s. To the left is an indication
1. Fluphenazine NOT AVAILABLE
of relative risks at equivalent doses. The differences in risk
2. Haloperidol
between drugs in categories 1- 4 are much smaller than the
3. Zuclopenthixol
difference in risk between categories 4-6. In fact with categories
4. Flupentixol (and Pipotiazine)
2-4 there is clinical evidence of no EPSE difference (Taylor, 2009).
5. Risperidone and paliperidone
Regarding just akathisia risk for aripiprazole would sit between
6. Aripiprazole and olanzapine
categories 4 and 5. Box C
Situations where Paliperidone or Aripiprazole LAI can
Reason
be considered.
1
If effectively treated with oral form of LAI, now
Good evidence of efficacy
or in the past. For aripiprazole LAI client should
be willing to take oral aripiprazole for 2 weeks
after first LAI dose.
Situations to consider trial of oral Risperidone or
-Trial of oral medication is recommended to demonstrate
Aripiprazole pending use of LAI, to demonstrate
response (Paliperidone) or tolerance (aripiprazole)
tolerability and/or effectiveness.
-Aripiprazole also requires the client to take an oral dose
for 2 weeks after first injection.
See longer guidelines on choice of LAI for non-orally compliant patients including those who have not
demonstrated recommended oral response or tolerance as specified above.(section 4 )
PG23 - Choice of Long-Acting Injectable Antipsychotic
Approved by Drug and Therapeutics Committee: October 2018
Review Date: October 2022
Page 4 of 12
2.
Current presentation or history of EPSEs or
tardive dyskinesia.
3.
Clients needing anti-cholinergic medicine with
antipsychotics. Anticholinergics can however be
useful while decreasing dose of antipsychotic or if
it is felt changing antipsychotic or decreasing
dose carries too high risk of relapse.
If diagnosis is bipolar or schizoaffective with
depressive symptoms now or in the past.
Poor response to FGA. If FGA ineffective or
having a flattening effect on mood, or worsening
negative symptoms or causing increased
substance misuse. Consider also previous anticholinergic side effects with FGAs.
Over 45 yrs. Also consider potential hypotensive
effects of paliperidone compared to other LAIs.
Aripiprazole may be a good choice.
4.
5.
6.
7.
Client having two or more of these risk factors
for T.D; substance misuse Inc. alcohol, negative
symptoms/neurocognitive deficits, L.D , ethnic
minority, FH of EPSE, diabetes.
Situations where Paliperidone or Aripiprazole LAI can
be considered (Cont.)
8
Try to avoid prolactin raising drugs if; under 25,
osteoporosis, or history hormone dependent
breast cancer. Also try to avoid long term use in
young women because of bone mineral density
and breast cancer risk. Consider aripiprazole.
9
10
11
12
13
14.
15.
Weight gain/Metabolic syndrome or high risk of
it.
First episode psychosis and/or under care of
STEPS team. Give client choice.
Client with history of abuse who will agree to
deltoid injections rather than gluteal
Rare cases where negative symptomology
dominates picture (e.g. simple schizophrenia)
If QTc prolongation or at risk of it, and or cardiac
issues.
HIGH RISK CLIENTS; Violent and a risk to the
public, or at risk of serious self-harm including
high overdose risk on oral antipsychotics. Clinical
indication rather than cost to drive choice.
Clients known to be allergic to the oil that a FGA
LAI is suspended in.
EPSEs, both early and late in the course of treatment, are
risk indicators for later T.D. C, E. For T.D morbidity and
mortality see D
Use of anti-cholinergics will not decrease risk of T.D. Long
term use can result in cognitive problems and during
acute psychotic phases, decreased effectiveness of
antipsychotic. (See Bazire pg.536) G. For anticholinergic
cardiac concerns see L
Higher risk of T.D in this group. Risk of depression with
FGA use. F
FGA may be ineffective. FGAs can have anhedonic effect.
Literature suggests, in some cases FGAs could, make
cravings worse for drugs misusers. A, F, G
Risk of T.D accelerates between 45-60 then levels off but
remains high. D, (appendix 1 and C also relevant).
Absolute cardiac risk is related to age for which
aripiprazole is a good choice. L
These risk factors have positive predictive value for T.D
and cumulatively are a concern. D
Reason
High prolactin leads to decreased bone mineral density
and peak bone mass development is at 25. Aripiprazole
does not elevate prolactin. Paliperidon/risperidone are
particularly high risk followed by FGAs. Low relative risk
(1.16) and low absolute risk of breast cancer with
prolactin elevating drugs as a whole, so benefits may well
outweigh risk. If high risk drugs used ensure monitoring of
prolactin levels. H
Aripiprazole recommended in Maudsley guidelines
(Taylor, 2012) B. Also relevant L
First episode client group has good response rate to
antipsychotics, but are sensitive to side effects. Side
effects at this point have a big impact on long term
compliance. Aripiprazole a good option. I
All paliperidone and aripiprazole injections can be given
into deltoid. J
FGAs in certain cases potentially better for negative
symptoms. G
Aripiprazole is a good choice. Increasing cardiac disease
with age. L. Appendix 1 and end of this table relevant
Akathisia can lead to aggression. SGA usually more
appropriate than FGA to manage certain personality
disorder traits.(Rare use of antipsychotics in P.D. alone
SEE FULL GUIDANCE) A, E, K
Flupentixol and Zuclopenthixol LAIs in vegetable oil from
coconuts. Other FGA LAIs in sesame oil.
PG23 - Choice of Long-Acting Injectable Antipsychotic
Approved by Drug and Therapeutics Committee: October 2018
Review Date: October 2022
Page 5 of 12
Situations where Olanzapine LAI to be considered.
1.
If effectively treated with oral olanzapine, now
Good evidence of efficacy
or in the past.
Because of the phenomenon of post injection syndrome and the need for 3 hours of monitoring after each injection,
local arrangements for this monitoring, and a venue for long term repeat injections, must be arranged prior to
prescribing. Refer to Clinical Protocol CP28 ‘Protocol for Olanzapine Long Acting Injection’ for the prescribing,
administration and monitoring procedures required with this product.
The LAI has shown equivalent efficacy/side effects to oral (Kane, 2010). The benefits of using it for those with high
risk of T.D, and those with a mood element to their presentation, are likely to be greater than benefits seen with
Paliperidone (Novick, 2010). Olanzapine LAI will have similar EPSE risk to aripiprazole but the lowest rate of
akathisia. The downside is weight gain and metabolic syndrome. A, B, N
Situations where Risperidone LAI to be considered.
Because of the practical advantages of Paliperidone over Risperdal LAI, with little cost difference, the initiation of
Risperdal LAI is no longer recommended for new presentations. For patients stabilised on Risperidone LAI changing
them to Paliperidone LAI at the equivalent doses recommended in the SPC could result in a slight dose reduction, so
caution is recommended. There is a comparison of the two drugs in appendix 2.
Other prescribing issues not specifically covered above.
Cardiac risk, risk of venous thromboembolism (see appendix 1), TIA/CVA, hypertension, epilepsy, glaucoma, sleep
apnoea, sexual dysfunction, liver failure and renal failure etc. Choice of best antipsychotic does not necessarily
follow a FGA/SGA divide for some of these issues. See The Psychotropic Drug Directory (Bazire, 2014 Chapter 3).
Regarding Neuroleptic malignant syndrome – mortality may be lower with SGA’s (Taylor, 2012 pg. 110)
Sudden Cardiac Death.(SCD) Oversimplifying a complicated area the main things to consider as predictors are;
1. QTc interval
2. Orthostatic hypotension. (Linked to increasing myocardial Infarction risk, Luukinen, 2004). Bazire pg. 505
states tolerance usually develops.
3. Tachycardia which may be compensatory to avoid orthostatic hypotension (Drugs & Therapy Perspectives,
2012). Alternately tachycardia may be linked to anticholinergic effect of the drug which often remits over time
(O’ Brien 2003). Whatever the cause, tachycardia in an already diseased heart can be a problem.
4. Age/Cardiac history (Ray 2009, found rates of SCD 10 times greater in 70-74 year olds compared to 30-35 year
olds). High likelihood IHD in elderly population.
There is a lack of conclusive data of differences between antipsychotics regarding SCD risk. QTc risk is variable
amongst antipsychotics as is risk of orthostatic hypotension and tachycardia. Aripiprazole is likely to be the safest
as it is unlikely to affect QTc, or blood pressure. Whatever is used it is important to monitor ECGs and lying/standing
BP and pulse, bloods) and look for other risk factors for raised QTc. See also Table 3 and BOX L
2. Procedure for prescribing SGA LAIs
If Aripiprazole, Paliperidone, or Olanzapine LAI is considered appropriate then the prescriber must
adhere to Standard Operating Procedure MM26 ‘Prescribing Non-Approved Medications’.
For Non-Approved Medicines follow SOP MM26
Particular care is required in completing the sections relating to previous treatment and why this person
requires an SGA. If the client meets risk criteria from section 15 please highlight this clearly.
PG23 - Choice of Long-Acting Injectable Antipsychotic
Approved by Drug and Therapeutics Committee: October 2018
Review Date: October 2022
Page 6 of 12
3. Licencing.
For FGA LAIs a test dose is recommended for all except Haloperidol where in the SPC there seems to be an expectation
of prior oral treatment. The SPC for Flupentixol LAI states that those starting should be first stabilised on oral therapy.
For the SGA LAIs there is an expectation in the SPCs that prior oral tolerance is demonstrated, and in the case of
paliperidone, prior oral effectiveness of risperidone.
Table 2
LAI
Licenced BNF
Indication
Prior oral treatment specified
in SPC
Fluphenazine
NO LONGER
AVAILABLE
Haloperidol
Maintenance in
schizophrenia+
other psychosis.
Maintenance in
schizophrenia +
other psychosis.
Not specified
Zuclopenthixol
Maintenance in
schizophrenia +
other psychosis.
Maintenance in
schizophrenia+
other psychosis
Flupentixol
Caution in
agitated client
Pipotiazine
Risperidone
Not for new
initiation
Paliperidone
(Xeplion)
Schizophrenia
or psychoses
Maintenance of
schizophrenia
Test
dose in
SPC
Yes
Licenced
Route SPC
Time to
peak
(days)
1-2
1
Half-life
(days)
Implied. SPC states the initial
dose is determined by the
amount of oral medication
required to maintain the patient
before starting LAI treatment.
Not specified
No
(25mg
recomm
ended)*
Gluteal
3-9
7
21-28
21
Yes
Gluteal or
lateral thigh
4-9
7
7
14
Those stabilised on oral therapy.
Yes
Gluteal or
lateral thigh
7-10
3-7
7
17
Gluteal or
deltoid
35
28
?
First 2
injections
into deltoid.
Then gluteal
or deltoid.
Gluteal or
deltoid
13
29-45
30-33
84-95
(deltoid)
118-130
(gluteal)
30
(range
13-42)
14-28
46.5
Product discontinued
Patients tolerant to risperidone No
by mouth. Also needs oral cover
for at least first 3-4 weeks.
Patients previously responsive
No
to risperidone or paliperidone.
(or currently responsive by
inference)
Gluteal
Trevicta (once
every 3 month
preparation of
paliperidone)
See below for
dosing
information.
Olanzapine
Maintenance of
schizophrenia
Maintenance of schizophrenia in
patients who are clinically
stableon once monthlyIM
paliperidone
No
Maintenance in
schizophrenia
Those tolerant and responsive
to oral olanzapine.
No
Gluteal
2-4
2-4
Aripiprazole
Maintenance
treatment of
schizophrenia
for adults
stabilised with
oral
aripiprazole.
SPC states for those who have
never taken aripiprazole,
tolerability orally should be
demonstrated before the LAI is
started. Oral aripiprazole 1020mg should be maintained for
14 days after the LAI is
No
Gluteal
or deltoid
14
14
7-14
PG23 - Choice of Long-Acting Injectable Antipsychotic
Approved by Drug and Therapeutics Committee: October 2018
Review Date: October 2022
Page 7 of 12
administered to maintain
therapeutic concentrations.
- Figures in black from Bazire (2014 or 2018), and in blue from Taylor (2009). Figures in green from elsewhere.
- * Test dose is not stated in SPC. Maudsley suggests 25mg (Taylor, 2015 pg. 67)
AS ABOVE TREVICTA SHOULD ONLY BE GIVEN TO CLIENTS ALREADY STABILISED ON MONTHLY PALIPERIDONE
(xeplion). If creatinine clearance 50-80 ensure Xeplion has been correctly optimised before any switch. The
following is taken from the SPC at https://www.medicines.org.uk/emc/product/7230/smpc
TREVICTA is designed to deliver paliperidone over a 3-month period, while 1-monthly paliperidone palmitate
injection is administered on a monthly basis. TREVICTA, when administered at doses that are 3.5-fold higher than
the corresponding dose of 1-monthly paliperidone palmitate injection (see section 4.2), results in paliperidone
exposures similar to those obtained with corresponding monthly doses of 1-monthly paliperidone palmitate
injection
TREVICTA should be initiated in place of the next scheduled dose of 1-monthly paliperidone palmitate injectable (±
7 days). The TREVICTA dose should be based on the previous 1-monthly paliperidone palmitate injectable dose
using a 3.5-fold higher dose shown in the following table:
TREVICTA doses for patients adequately treated with 1-monthly paliperidone palmitate injectable
If the last dose of 1-monthly paliperidone palmitate
injectable is
Initiate TREVICTA at the following dose
50 mg
175 mg
75 mg
263 mg
100 mg
350 mg
150 mg
525 mg
There is no equivalent dose of TREVICTA for the 25 mg dose of 1-monthly paliperidone palmitate injectable which
was not studied.
Following the initial TREVICTA dose, TREVICTA should be administered by intramuscular injection once every 3
months (± 2 weeks, see also Missed dose section).
If needed, dose adjustment of TREVICTA can be made every 3 months in increments within the range of 175 mg to
525 mg based on individual patient tolerability and/or efficacy. Due to the long-acting nature of TREVICTA, the
patient's response to an adjusted dose may not be apparent for several months (see section 5.2). If the patient
remains symptomatic, they should be managed according to clinical practice.
Switching from other antipsychotic medicinal products
TREVICTA is to be used only after the patient has been adequately treated with 1-monthly paliperidone palmitate
injectable preferably for four months or more.
4. Choice of LAI for non-orally compliant patients including those who have not
demonstrated recommended oral response or tolerance as specified above (1)
For these clients there is a different risk benefit analysis.
Non orally compliant patients.
PG23 - Choice of Long-Acting Injectable Antipsychotic
Approved by Drug and Therapeutics Committee: October 2018
Review Date: October 2022
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For some, oral non-compliance may be due to chaotic lifestyle, forgetfulness etc. If a LAI requiring evidence of
oral tolerance or effectiveness is being considered, and the client cannot reliably demonstrate this
tolerance/effectiveness in the community, admission could be helpful to establish tolerance/response orally
before administration of the LAI. However another group of clients will be non-compliant even during admission.
It is this second group that will be considered below.
Maudsley states; “Depot preparations are not recommended for those who are antipsychotic naïve” but LAIs
cannot always be avoided in this situation.
Things to bear in mind with the FGAs for those who have not shown tolerance are;
Table 3
1.
2.
3.
4.
Despite the fact that most FGAs are licenced when oral tolerance has not been demonstrated, they are
more likely than SGAs to cause acute dystonic reactions. A test dose is recommended to check for the
likelihood of EPSE as the nature of LAIs means any side effects will be long lived, however as test doses
of FGAs are low and they will not necessarily identify many of the people who go on to develop EPSEs
on treatment doses.
Flupentixol can be agitating and that is probably why the SPC recommends that oral tolerance is
demonstrated.
Allergic reactions to FGAs are probably more likely than to SGAs, as people can be allergic to the oil
that FGAs are dissolved in (vegetable coconut oil or sesame oil). The test dose should also identify those
who are allergic. SGAs have an aqueous base “not known to be allergenic” according to Maudsley
guidelines (pg. 41)
Regarding Neuroleptic malignant syndrome – mortality may be lower with SGA’s (Maudsley pg. 110)
So it would seem when a client is orally non-compliant and has not previously shown tolerance orally to an
antipsychotic that comes in the form of a LAI that an SGA would be preferable. However as we have seen in the
licencing conditions this is tricky. The reason for extra licencing restrictions of oral tolerability or effectiveness
tests for Aripiprazole, Paliperidone and olanzapine may be because they have longer half-lives than the FGAs,
so theoretically side effects could be prolonged. However it also probably reflects stricter licencing conditions
since the FGAs were marketed (half-lives of haloperidol and pipotiazine are not a lot less.) On the positive side
longer half-lives mean less erratic changes in blood levels which may in theory be beneficial regarding side
effects.
Often we want to use LAIs exactly because of non-compliance or refusal. Prescribers may still want to use the SGA
LAIs when an oral trial has not been done, but the use will be off licence and a thorough risk benefit analysis
needs to be done and documented. An article by Baldwin & Kosky (2007) provides useful information on “Offlabel prescribing in psychiatric practice” and how it can often be of benefit to clients.
Table 4. Things to bear in mind with the SGAs for non-orally compliant clients (don’t
forget to consider half-life).
SGA LAI
Risperidone
Aripiprazole
Use in orally non-compliant patient
This should not be used in a non-orally compliant patient as a minimum of 3 weeks full
oral cover is needed after the first injection before tapering off the oral dose can occur.
Clients who have never taken aripiprazole orally. There are a few reasons why it is
advisable not to use without oral tolerance being demonstrated. The half-life of
Aripiprazole LAI is the greatest of all the LAIs. There is potential for akathisia and the
Half life
?
46.5
days
PG23 - Choice of Long-Acting Injectable Antipsychotic
Approved by Drug and Therapeutics Committee: October 2018
Review Date: October 2022
Page 9 of 12
fact that it is non-sedating, means there may not be a counterbalance to that akathisia
for a client unwilling to take oral benzodiazepines. (however akathisia is probably still
less likely to be a problem than for FGAs) Additionally as 8 percent of the population
are CYP2D6 poor metabolisers this will affect aripiprazole’s metabolism, so it could be
detrimental to give them the full 400mg. IF USED OFF LICENCE
Clients with previous response/tolerance to aripiprazole. Clinical trials studied
effectiveness in cohorts stabilised on oral aripiprazole before the first injection, who
also have two weeks oral cover after the injection See box N. Due to a slow rate of
absorption, if Aripiprazole LAI were to be given without the oral cover according to
Mallikaarjun (2013) it takes 14 days to reach therapeutic levels.
A thorough risk benefit analysis is vital. Despite these drawbacks the need to give a
test dose of FGAs also delays response, and there could be an argument for oral cover
for some of the FGA LAIs that take a while to reach peak concentrations.
OFF LICENCE INDICATION IF USED IN THIS CLINICAL SCENARIO
Paliperidone Clients who have shown tolerance and effectiveness to previous use of risperidone or 29-45
(Xeplion)
paliperidone. The SPC for paliperidone recommends evidence of “effectiveness” and no days
oral cross cover is necessary after the LAI is given, so in this situation paliperidone LAI
will probably be the treatment of choice. WITHIN LICENCE
Clients who have shown tolerance to previous use of risperidone or palioeridone but
not stayed on it long enough to demonstrate efficacy. In many of the trials for
paliperidone only tolerance was demonstrated before use of the LAI. When only
tolerance has been demonstrated paliperidone may still be preferable to other LAIs for
which prior oral tolerance has not been demonstrated regardless of the risk factors on
table 1. In this scenario paliperidone may represent the safer option due to knowledge
of this tolerance. However consider also that short term tolerance does not necessarily
equate to long term tolerance.
OFF LICENCE INDICATION IF USED IN THIS CLINICAL SCENARIO
For clients in whom risperidone or paliperidone tolerance has not been established
consider using paliperidone LAI if it is felt using a FGA could be harmful. Switching the
day 1 (150mg) and day 8 dose (100mg) around for paliperidone would give you a test
dose which in theory is approximately equivalent to a test dose of pipotiazine
(calculated from Woods, 2013; and Maudsley pg.14) There is no actual trial evidence to
back up dosing in this way for safety or effectiveness.
OFF LICENCE INDICATION IF USED IN THIS CLINICAL SCENARIO
Paliperidone Do not use in this client group
84-130
(Trevicta)
Olanzapine
Clients not demonstrating oral previous response or tolerance. Consider that, if using
30
olanzapine LAI, without having demonstrated oral tolerability if a client does develop
days,
post injection syndrome this could be more dangerous for them than those who have
range,
known oral tolerance. OFF LICENCE INDICATION IF USED IN THIS CLINICAL SCENARIO
13-42
-Always be careful using any LAI FGA or SGA where tolerance is not known as all antipsychotics have
arrythmogenic potential. If previously used check to see if there were any cardiac concerns or ECGs done at that
time.
-Consider that oral trials can be ineffective because of covert intermittent non-compliance, and even partial
response in poorly compliant groups could be a sign of effectiveness (Alphs, 2013)
Control and Restraint (C&R) situation- Often when a client is orally non-compliant they will also
require control and restraint. For these clients there is a different risk benefit analysis
Table 5. Considerations for control and restraint in choice of LAI.
1.
Because of the logistics of C&R giving deltoid injections in these circumstances is probably always
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2.
3.
4.
inappropriate. It is hard to restrain someone in an appropriate position and more risk of accidental
nerve/vessel damage or injury to nursing staff. Paliperidone is licenced only for deltoid injections for the
first 2 injections.
For paliperidone the gluteal route could be used (off licence for first 2 injections) but this could delay
response and prolong half-life. (However the need to give a test dose of FGAs also delays response.)
The risk of post injection syndrome, is believed to be associated with accidental intravascular
administration of a portion of the dose, most likely following vessel injury during injection process (Detke,
2010). One could postulate that risk of this happening may be increased in a control and restraint situation
when an individual is resisting treatment. Correct injection technique is important and great care is needed
to ensure there is minimal movement of the client if Olanzapine Lai is administered in this way.
QTc can be prolonged in the stress of a C&R situation. (Bazire pg. 249)
Differences between FGA LAIs in the acute situation.
Table 6. Adapted from Bazire pg.211, Maudsley pg151 and Taylor (2009). Equivalent doses calculated using table
in Maudsley Guidelines pg. 14. Sedation estimates from Maudsley pg.151.
LAI
Time
Time
Half-life HalfTest
Test dose
BNF guidance Sedation
to
to
(days)
life
dose as equivalence to on time to
Estimate
peak
peak
Bazire
(Taylor per BNF pipotiazine
wait until
(Maudsley)
Bazire Taylor (2014)
2009)
25mg
second dose.
Pipotiazine
Product now discontinued
Fluphenazine
1-2
1
14
7-14
12.5mg 100%
4-7
+
NO LONGER
AVAILABLE
Zuclopenthixol 4-9
7
7
14
100mg
40%
7 days at
++
least
Haloperidol
3-9
7
21-28
21
?25mg
66%
?
+
Flupentixol
7-10
3-7
7
17
20mg
80%
7 days at
+ (can be
Caution in
least
stimulating)
agitated client
Clinical relevance of the information above is uncertain so suggestions given below are speculative.
Re. Fluphenazine Saklad (2013, pg. 3) states dose dumping can occur. Ellingrod (2012) states it has; “considerable
inter-patient variability in absorption rate and peak effects, and a relatively short duration of action. Dosing every
7 days may be necessary to avoid peak plasma level adverse effects or symptom recurrence”.
Re. Zuclopenthixol Taylor (2009 pg. 14) states, “marked differences between peak and trough plasma levels
when given every 2 weeks (peak levels more than 3 times higher than trough)”
Sedation. Zuclopenthixol and fluphenazine may be seemingly more sedative than pipotiazine due to their short
time to peak and may help explain higher levels of EPSE with fluphenazine and possibly zuclopenthixol. Because
of likely peaks and troughs caused by these 2 drugs, theoretically they may be better dosed at less than 4 weekly
in some. Clinical outcome evidence has not been uncovered to support this assertion, but the BNF gives more
flexible dosing intervals for the Fluphenazine, Zuclopenthixol and Flupentixol FGA LAIs.
See end of table 1, and BOX L
Box M contains suggested guidelines for monitoring treatment with an LAI, taking into account, cardiac risk,
T.D risk and hyperprolactinaemia.
5. Monitoring
Individuals who are prescribed antipsychotic medication (any formulation) must be offered appropriate and
timely physical health monitoring as well regular review and discussions about side effects and tolerability of
treatment. Refer to Practice Standard PS11 ‘Physical Health Monitoring’ for recommended monitoring and
review frequencies.
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Lack of patient compliance with monitoring should not usually lead to withholding treatment. In this situation
the benefits of maintaining mental health need to be balanced against the risk of continued prescribing and
administration in the absence of physical monitoring (which could result in a greater incidence of adverse effects)
Due to the long duration of action of antipsychotic LAIs (and greater difficulty in modifying dose) QTc
prolongation, tachycardia and orthostatic hypotension are particularly an issue. Risk of Sudden Cardiac death is
usually dose related. Consider factors in box J section 1. Tolerability of the drug may be unknown. Some trials
indicate that for FGAs risk of SCD is greatest in the first year especially in the first 2 months after starting
antipsychotic. (Wang 2005, Murray 2013). Monitoring this period is important as SCD secondary to QTc
prolongation is more likely in the early stages of treatment (Murray, 2013).
Taken from Wang (2009) in over 65s. (See appendix 1 for more information on this study, may not be
representative of LAIs we use. However it demonstrates the need for monitoring early on.)
Wenzel (2012) suggests telling the patient to pay “attention to potential electrolyte loss caused by diarrhoea,
vomiting, profuse sweating, undernourishment, diuretic therapy, alcohol and or drug use, and eating disorders.”
Where care is transferred between care providers, any monitoring required (appropriate to the condition
and/or any prescribed medication) must be clearly communicated to the clinician accepting the responsibility
of on-going prescribing and review of treatment.
In addition to monitoring recommended for all antipsychotics in practice standard 11 when starting an LAI it is
recommended to check magnesium at baseline as that can effect QTc. As well as a baseline ECG one should be
taken at around the time of an initial peak level after the first dose and when the client has reached an
estimated steady state. Consider an ECG after significant dose increases. Blood pressure checks should be lying
and standing as orthostatic hypotension can be a problem. As clients are most often commenced on LAI’s in
hospital these extra checks should not constitute much difficulty.
6. Tolerability and adverse effects
Client groups not mentioned in the categories in table 1 may also benefit from an SGA LAI. For example
although older people are at higher risk of Tardive dyskinesia; if younger clients get it, it is likely to be more
socially debilitating for them. Also as we have seen from Wood (2010) and Dilip (1999) that exposure to an FGA
for at least a month (perhaps more) probably predisposes a client to T.D if they stop that antipsychotic and start
one again later (see box C). Additionally waiting for side effects to occur and then changing medications can lead
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to disruption of treatment and the risk that the new treatment may be less likely to work, compared to if a
treatment deemed most appropriate is used earlier on (see box I, last paragraph).
Figure 1. Taken from Leucht meta-analysis (2013).
As the SGAs are generally well tolerated
(see Leucht 2013 below), potential
advantages to primary care include more
stable clients and more satisfied relatives.
There is emerging evidence for
aripiprazole that it offers advantages with
regards to long term cardiovascular risk
and mortality which is not surprising
considering its side effect profile.
Increased use could potentially benefit
primary care with regards to treatment of
arrhythmias, diabetes, hyperlipidaemia
and other health conditions that can be
associatied with antipsychotic
prescribing. (See Box L – section 6). As
LAIs are often used in difficult cases, use
of more tolerable LAIs could even impact
on violent and aggressive incidents
towards primary care staff (see box K, E)
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7. Evidence boxes to support Table 1.
A. Effectiveness of and Switching antipsychotics. (5,14)
Figure 2. Taken from Leucht meta-analysis (2013).
LAIs Compared to each other in oral form.
The above meta-analysis data mostly reflects the antipsychotics in oral form. Kishimoto (2012) demonstrated that
in randomised control trials (where compliance with oral meds is highly likely), effectiveness of LAIs is equivalent
to their oral form and in the real world with partial compliance common they are probably more effective
(Kishimoto, 2013). Leucht’s (2013) results are supported by Essock (2006) who did a re-analysis of CATIE (Clinical
Antipsychotic Trials of Intervention Effectiveness, Lieberman 2005) data. The CATIE trials involved patients either
staying on their original medications or switching to a new one. Essock showed that individuals switched from
olanzapine or risperidone, to other antipsychotics, tended to do worse than those allocated to stay on
risperidone or olanzapine. Conversely she states those originally on quetiapine tended to do better if switched to
olanzapine. She does not mention other specifics. This chart therefore could help in situations where a change in
antipsychotic is needed because of lack of efficacy. It cannot however be ruled out that changing from a drug
higher up the scale to one lower down will never show benefit, considering that some drugs may have
significantly differing mechanisms of action and the information from Essock is limited.. However based on the
above trials, with regards to switching for the sake of efficacy the Maudsley Guidelines (Taylor, 2012) pg. 45
states; ”if patients have already tried olanzapine and risperidone the benefits of switching rather than staying are
probably marginal”
We can see the effectiveness of aripiprazole seems to be equivalent to haloperidol. Maudsley Guidelines (2012
pg. 42) states the FGA LAIs have been proven to be similarly efficacious to each other, except that zuclopenthixol
LAI may be slightly more efficacious than the other FGA LAIs.
Direct trials between specific FGA and SGA LAIs are few. A retrospective study (Shajahan 2010)
demonstrated Risperidone LAI and Flupentixol LAI improved GCI scores to a greater extent than zuclopenthixol
LAI, but zuclopentixol was better at decreasing time to relapse. The retrospective nature of the trial means little
can be interpreted from it. In another retrospective trial Lammers (2013) found that Risperidone LAI had very
significantly less EPSE than FGA LAIs. Rubio (2006) showed a superiority of Risperidone LAI to Zuclopenthixol LAI
in an open randomised study of clients with co-morbid substance misuse. Rubio (2006) cited other trials
suggesting that Risperidone orally was better than Zuclopenthixol orally for negative symptoms. An unpublished
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analysis (Taylor, 2013) from prospective data for clients put on paliperidone LAI in the South London and
Maudsley Hospital shows that clients seem to stay on Paliperidone LAI for significantly longer than risperidone
LAI, probably reflecting practical advantages of paliperidone LAI (see appendix 2)
LAI compared to oral medication. By performing a meta-analysis of *mirror-image trials Kishimoto (2013) claims
to have shown that LAI’s as a group perform a lot better than their oral counterparts. (There are also published
preliminary results (Kane, 2013) from an as yet unfinished aripiprazole mirror image trial with similar results to
Kishimoto, but it will be prudent to wait for publication of the full trial before coming to too many conclusions.)
These results contradict Kishimoto’s (2012) meta-analysis of RCTs finding equality between LAI and oral
antipsychotics (mentioned earlier). In RCTs clients in the oral cohorts are likely to take their medications, but in
the real world it has been shown (Docherty, 2002) that full medication compliance is very poor and partial
compliance is the norm, hence the benefit of LAIs in real world scenarios demonstrated in the “mirror image”
trials. A term often used in the field is “covert non-compliance” as the prescriber is often unaware. The graph
below taken from Weiden (2004) shows how missing small numbers of tablets in one year can impact relapse
rates. The quality of these trials has not been assessed in detail here as the focus of this document is deciding
between LAIs not if one is indicated.
*Mirror image trials look at how well someone does regarding relapse on oral medication then how well they do
when changed to an LAI. Each subject is his own control. As with all types of trial they have their limitations but
with LAIs they are thought to pick up better on real world scenarios.
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B. Weight gain/Diabetes/Dyslipidaemia, and Switching antipsychotic. (9)
Figure 3. Taken from Leucht (2013)
Weight. As we can see for weight gain haloperidol has the best profile, olanzapine the worst. The above
evidence shows that the concept of the FGA/SGA divide regarding weight gain no longer stands.). Lai (2009)
found that switching from an FGA to Risperidone LAI resulted in some weight gain, but this could be explained if
there people on haloperidol in the original cohort. Regarding antipsychotic induced weight gain Maudsley state,
“there is fairly strong support for switching to aripiprazole”.
Diabetes. Maudsley guidelines (pg. 151) rate Risperidone, Piportil, Flupentixol, and zuclopenthixol as equal risk
of diabetes. Aripiprazole has a similar metabolic risks to haloperidol. However risk of EPSE/T.D and cardiac risk for
haloperidol make it potentially a poor choice. Haloperidol may be more likely than aripiprazole to cause diabetes
(Maudsley pg. 135). Maudsley pg. 134 states that aripiprazole is “cautiously recommended for those with a
history or predisposition to diabetes mellitus, or as an alternative to other antipsychotics known to be
diabetogenic.
Hyperlipidaemia. Hypeprolactinaemia is theoretically linked to dyslipidaemia. A trial quoted in Maudsley pg.
139 found risperidone to have less dyslipidaemia than FGAs and to be equal to controls. The Maudsley stated
equivalence of risperidone, pipotiazine, flupentixol and zuclopenthixol for weight is probably also true for
hyperlipidaemia but evidence is lacking (see Maudsley pg. 139). With regards to dyslipidaemia the Maudsley
guidelines pg. 140 states “Aripiprazole seems at present to be the treatment of choice in those with prior
antipsychotic –induced dyslipidaemia”.
CHD. It is logical to assume the above risk factors translate to greater CHD risk. Bazire (2014. Pg. 248, quoting
Daumit, 2008 figures) states the CATIE trial found a similar 10 year CHD risk for risperidone and Perphenazine
(they actually decreased risk slightly but olanzapine increased it.) See box L and key uncertainty below.
Changing Antipsychotic. Figure 1, in evidence Box A suggests care is needed if we are moving from an
antipsychotic further to left on the chart to one further to the right, as a movement in that direction could mean a
risk of relapse. This does not mean it should not be done especially if someone has debilitating side effects.
Trials that have looked at switches from other antipsychotics to aripiprazole because of weight gain have not
shown increase in illness relapse, although Stroup (2011) found a greater level of drop out from antipsychotic
medication after the switch. Bazire (2014) pg. 210 states that switching to aripiprazole should not be abrupt and
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that switching from FGAs/D2 specific antipsychotics to aripiprazole may be difficult. There should be a very
gradual switch.
Maudsley (pg. 511) quoting Trifiro (2009) states that the effects of metabolic syndrome tend to be attenuated
with advancing age and in elderly patients with dementia. One paper to back up that statement; Lieberman
(2004) demonstrates that the diabetes risk with antipsychotics drops off a bit after 70 years of age.
KEY UNCERTAINTIES.
-If and when and to what degree there is attenuation of Metabolic syndrome in later life.
-Side effect profiles suggest risperidone will have a similar metabolic profile to pipotiazine, flupentixol and
zuclopenthixol. Direct comparison trials are lacking. From the evidence it is reasonable to assume they are similar
-If some antipsychotics decrease coronary heart disease risk (Daumit, 2008), despite metabolic effects (e.g.
risperidone) perhaps explained by better compliance with medical care and lifestyle changes after effective
treatment. More evidence is needed. See section on Sudden Cardiac Death risk as risperidone, along with many
other antipsychotics seems to increase overall cardiac risk.
C. Antipsychotics and Extra Pyramidal Side Effects (EPSEs)/Tardive Dyskinesia (T.D)
risk (2, 6).
Going from high to low risk for EPSE and T.D
1. Fluphenazine NOT AVAILABLE
2. Haloperidol
3. Zuclopenthixol
4. Pipotiazine and Flupentixol
5. Risperidone and Paliperidone.
6. Aripiprazole and Olanzapine
EPSEs (akathisia, parkinsonism, dystonia, etc.)/T.D are the major
concern when prescribing 1st generation LAI’s. To the left is an
indication of relative risks at equivalent doses. The differences in
risk between drugs in categories 1- 4 are much smaller than the
difference in risk between categories 4-6. In fact with categories 24 there is clinical evidence of no EPSE difference (Taylor, 2009).
Regarding just akathisia risk for aripiprazole would sit between
categories 4 and 5.
EPSE.
There is evidence to suggest that FGA LAIs cause more EPSEs than their oral counterparts (Novick, 2010)*. This
is probably because FGAs have a narrow therapeutic dosing range between effective dose and side effect dose. It
is especially hard to hit this dosing range in LAI form. This is not the case with paliperidone and olanzapine which
have wider therapeutic dosing ranges, and so they will have no higher EPSE rates in their LAI form than oral
forms. In fact Alamo (2013) and the Maudsley guidelines (pg. 44) cite evidence that Risperidone LAI actually has a
lower side effect burden than its oral counterpart. Kane (2010) shows the tolerance of olanzapine LAI is the same
as oral. Aripiprazole’s unique method of action means the same relationship between oral and LAI forms does not
apply. Trials have differed in their outcomes when comparing the LAI to oral form. Overall it seems Aripiprazole
LAI may cause 1/3 more EPSE than its oral form (Otsuka, 2014, Summary product characteristics). However
Aripiprazole LAI will still be less likely to cause EPSE that paliperidone and Risperidone LAI. Even in its oral form
aripiprazole has a particular problem with akathisia (see box E) and is the worst culprit among the SGAs for
causing this (Maudsley pg. 100).
Regarding differences between individual FGA LAIs Taylor (2009) states; “Pipotiazine palmitate (mean dose 65
mg per month) has been shown to cause similar rates of extrapyramidal symptoms as haloperidol decanoate
(mean dose 100 mg per month): 36% and 29% respectively. In the same study weight gain of more than 5 kg was
more common in those receiving pipotiazine (39% v. 16%). As a piperidine phenothiazine, pipotiazine might be
expected to show a low incidence of extrapyramidal symptoms. There is limited evidence that pipotiazine has a
relatively low potential for causing these symptoms compared with other LAIs.” This limited evidence is based
on a 1983 review, by Burch, not a trial. The Burch paper is currently unavailable but has been ordered. Taylor
goes on, “A meta-analysis of comparative trials of FGA–LAI doses revealed no differences in the rates of
extrapyramidal symptoms and tardive dyskinesia compared with oral medication and few important differences
between individual LAIs. Other sources suggest an increased incidence of extrapyramidal symptoms and tardive
dyskinesia with LAIs compared with oral antipsychotics. Both reviews reported an increased risk of movement
disorders with fluphenazine decanoate compared with other FGA–LAIs.” Perhaps the individual differences we
would expect to see between the individual FGA LAIs is cancelled out by the difficulty of fine tuning doses of
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these drugs in LAI form.
*Novick’s paper if read in this context seems to underestimate the difference between FGAs and SGAs EPSEs due
to selection bias which the author admits.
Figure 4. Taken from Leucht meta-analysis (2013)
Tardive Dyskinesia
Differential risk profiles of the LAIs
FGAs vs Risperidone. Yearly Incidence of tardive dyskinesia given in Maudsley pg. 100 is 5% per patient
year for FGAs. This is a reference to work done by a task force of the American psychiatric association (1993).
Novick (2010 pg. 537-538) suggests this high incidence is maintained for the first 5 years, leading to a high
prevalence, and suggests that rate will be even higher with FGA LAIs (pg. 536). Estimates of incidence for
risperidone LAI are in the range of 0.7-1.19. (Harrison, 2004, Taylor 2009 referencing Gharabawi, 2005).
One could argue that the above data on the FGAs is skewed as we cannot be sure of the doses used. However in a
review, Taylor (2000) suggested “typical (FGA) antipsychotics cannot be used effectively without giving rise to
typical adverse events. Moreover low but effective doses seem to cause as many ‘typical’ averse events than
higher doses”. (However dose is important with regards to sudden cardiac death, Ray 2009). More recently
Schooler (2006) compared oral risperidone and haloperidol, with a haloperidol dose so low it was poorly
efficacious. Even with this very low dose of Haloperidol, it was 2.5 times more likely to cause T.D than
Risperidone (Gharwabawi,2006)
Risperidone LAI vs Pipotiazine LAI.As Pipotiazine theoretically is the FGA LAI least likely to cause T.D and
Risperidone/paliperidone the SGA LAIs most likely to cause T.D it seems sensible to estimate the relative risk.
Morganstein (1993) compared rates of T.D between haloperidol and the phenothiazines and found haloperidol
was 1.5 times more likely to cause T.D. Piportil is a phenothiazine. Schooner’s and Morganstein’s results
combined suggest that pipotiazine would be twice as likely to cause tardive dyskinesia than risperidone. However
if we take into account that;
1) The dose of haloperidol in the Schooler trial was very low.
2) There are other trials showing pipotiazine to have similar rates of EPSE to Haloperidol LAI, (Taylor, 2009,
pg. 16 referencing Bechelli, 1985),
3) Rates of movement disorders with FGAs become exaggerated in LAI form, (Novick, 2010.)Pg. 536, graph
suggests FGA LAIs are 1.4 times more likely to cause T.D than oral FGAs)
then pipotiazine is likely to be about at least 4 times more likely to cause T.D than Risperidone or Paliperidone
LAI. Note, regarding the graph from leucht above that chlorpromazine is a low potency phenothiazine and is not
representative of the phenothiazines as a group.
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Other SGAs oral evidence. Miller (2007) found very low rates of T.D with aripiprazole (about 0.4%)
compared to rates of 9% for haloperidol. This gave a relative risk of 0.05. Woods (2010) found a rate of 0% for
aripiprazole with a very small sample size. Rates of T.D for olanzapine as quoted in the Woods trial, in his review
of the rest of the literature, were greater than aripiprazole but less than for risperidone (Woods 2010).
Considering Leucht (2013) found EPSE rates for olanzapine to be slightly less than for aripiprazole it is likely the
two drugs have a similar risk profile. Kane (2006) states the CATIE trial (Lieberman, 2005) did not pick up
differential rates of T.D between FGAs and SGAs because of major methodological flaws.
Previous exposure to FGAs attenuating later advantage of SGAs.
Woods (2010) states; “Previous studies suggest that the risk of TD with SGAs is one-quarter that of FGAs.” He
agrees that the difference is marked for those with an affective component, but he later states “Our findings
suggest that the incidence rate of TD with SGA antipsychotics, while modestly reduced, remains substantial, at
least in patients with prior conventional antipsychotic exposure who currently constitute the large majority of
patients at our facility.” He also states, “The major limitation of our study is that nearly all of our CMHC subjects
had lifetime histories of conventional antipsychotic exposure, often extensive and most of it occurring before
baseline examination. It is possible that prior conventional antipsychotic use could sensitize patients
subsequently receiving atypicals (SGAs) to be at higher risk than if they had been conventional-naïve.” Even in
this scenario he found olanzapine on its own to have a relative risk of 0.46 compared to FGAs, so the expected
advantages of olanzapine is attenuated but not obliterated.
Dilip (1999) suggests previous antipsychotic exposure predisposes to T.D. How long the previous exposure needs
to be to increase risk is unclear but he showed it would need to be certainly more than 28 days.
Predicting T.D with EPSE.
With regards to “early” EPSEs Sachdev (2004) found an odds ratio of 1.3 predicting later T.D. These were
neuroleptic I patients who were assessed for EPSE soon after starting the antipsychotic. Although not suggesting
great predictive power he stated “Our study may have some clinical implications. While it is impossible from the
presence of acute EPSE to predict which individual will definitely go on to develop TD, the presence of severe
EPSE early in the treatment should alert the clinician to an increased risk. Such patients should arguably be
managed with lower doses of antipsychotic drugs, preferably atypical ones”. Looking at clients on long term
antipsychotic treatment Novick (2010) found those who had EPSE at baseline had a hazard ratio of 1.7 for
developing tardive dyskinesia compared to those without EPSE at baseline. Diederick (2006) gave Hazard ratios of
1.6-2.0. He stated this meant that EPSE were neither sensitive nor specific enough to be relied upon to predict
T.D. He suggested measures aimed at reducing the risk for the whole population on antipsychotics, and
suggested drug combinations with fewer extrapyramidal side effects. Due to financial restraints, as we cannot
offer everyone an FGA LAI, the population approach taken in Table 1 has been to identify groups at particular risk
of T.D.
Crane (1972) found akathisia to be a predictor for T.D in FGAs but this is probably not be the case when
considering akathisia in aripiprazole as T.D rates for aripiprazole are so low.
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D. Other risk factors for tardive dyskinesia. (2,6,7)
General. Bazire (2014) pg. 533 lists the risk factors for tardive dyskinesia as follows; “length of exposure to
antipsychotics in the elderly, alcohol consumption, advancing age, being male, previous head injury, presence of
organic brain disease, structural brain damage, earlier drug induced Parkinsonism, akathisia or dystonias, being
left handed, being diabetic, concurrent affective or negative symptoms and having a parent with schizophrenia
who themselves has or had dyskinesia.” It is surprising that Bazire states T.D is more common in men as Novick
(2010) pg. 538, states “Most but not all previous studies report that women have a greater risk of T.D than men”
Age. With regards to age and tardive dyskinesia Woerner (1998) states for the over 55s that their risk is “three
to five times what has been found for younger patients, despite treatment with lower doses.” Dilip (1999) found
that those in the age range of 45-60 had annual incidence rates of T.D 34.1% on FGAs, which was slightly more
than for those over 60 years old (although the difference was not significant). Jeste (1995) found a cumulative
prevalence rate of 60% in a group consisting of individuals from 45 into old age. Johnson reviewed a small chronic
group (1982) conclude 45 to be the point at which risk increases. Smith (1980) found “TD in those younger than
60 years improved over three times as often as in older patients.” Sweet (1992) suggests that the incidence goes
up all the way through adulthood until about 60 where it then plateaus and may even decrease modestly
KEY UNCERTAINTY. The Jeste, Dilip, and Woerner trials were all in patients starting or restarting antipsychotics
past 45. For those stabilised on, and tolerating a FGA, LAI no evidence has not been collated, to suggest that when
clients turn 45 that their medication should be changed. Some evidence suggests that after 5 years on an FGA
your chances of developing T.D start to decline.
Tardive Dyskinesia Mortality and Morbidity.
Mortality. Ballesteros (2000) did a meta-analysis of the literature and found an odds ratio of 1.4, (95% CI = 1.11.8, p < 0.005) correlating T.D with mortality. Despite the odds ratio of 1.4 he concluded, “The conclusion of the
meta-analysis was that tardive dyskinesia must be considered a weak risk factor in terms of mortality. It remains
to be elucidated whether it is a risk factor on its own or just a surrogate for any unknown organic liability”.
Since then, Chong (2009), in 6 year prospective study found increased mortality in those with T.D (hazard ratio,
1.90; 95% confidence interval, 1.12-3.20). No specific mechanism was identified.
Dean’s (2009) study found correlation between tardive dyskinesia and mortality was insignificant once age and
treatment with a FGA was taken into account (RR 1.12 C.I 0.86–1.45).He states; “Those who were exposed only
to conventional antipsychotics were over twice as likely to die during the observation period as those who had
taken only atypical antipsychotics.” In his discussion he considers other literature that has compared mortality
between FGAs and SGAs and states “Whether the use of conventional antipsychotics is a consistent predictor of
shortened survival time is doubtful”
So we are left with a confusing picture; there may be an increased mortality with T.D, but T.D may be a
surrogate marker for vulnerability rather than a cause of premature death. It is also of course possible that the
2 factors work synergistically to increase mortality.
Morbidity. According to Maudsley guidelines (page 100) 50% of cases are reversible.
However it can take
years to go away and drug changes to treat it may supress rather than cure it. See Caroff (2011b) for a more
detailed review of these issues. Myslobodsky (1985) in a trial looking at T.D and cognitive deficits found 88% were
unaware of their T.D (anosognosia). Alexopoulos (1979) found none of 18 outpatients with T.D had complained to
their therapist. Eight were unaware of it (five of these were still psychotic). One could argue from this that, if
some people are not complaining about it, why worry about it. Gelder (2006, pg. 534) states that T.D is associated
with akathisia, and involvement of the muscles of respiration. Youseff (1987) found higher rates of respiratory
infection. Also there is the issue of stigma and social isolation; Margolese (2005) states clients have problems with
re-integration into society and the workforce. Chouinard (2006) associates T.D with depression and suicide.
Therefore it is worth monitoring for to try to do something about it early on.
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E. Akathisia. (2, 14)
Akathisia can be a predictor of violence. Seemuller (2012) associated it with suicidality. The propensity of
individual LAIs to cause akathisia probably correlates with their propensity to cause EPSE (apart from
aripiprazole). According to the Maudsley Guidelines (pg. 100) aripiprazole is the SGA most likely to cause
akathisia in oral form, although it is still rated as less likely than the FGAs to do so. Maudsley give a rate of 25%
amongst FGAs. Kasper (2003) found rates of 13% aripiprazole (30mg) vs 25% for haloperidol (10mg) over 52
weeks in oral form. Aripiprazole LAI is 1.5 times more likely to cause akathisia than it’s oral form (Fleishacker,
2012). FGA LAIs are 1.2 times more likely to cause EPSE than their oral forms (Novick, 2010). For akathisia then
the gap between aripiprazole LAI and FGA LAIs may be decreased a bit, and the fact that some FGAs have more
sedating properties than aripiprazole, may mean if you get akathisia with one of them it is less apparent. However
it is likely that aripiprazole LAI is still less of a risk for akathisia compared to all the FGA LAIs.
In the SPC for Aripiprazole LAI section 4.8 it states, “Akathisia was the most frequently observed symptom (8.2 %)
and typically starts around day 10 after first injection, and lasts a median of 56 days. Subjects with akathisia
typically received anti-cholinergic medicines as treatment, primarily benzatropine mesilate and trihexyphenidyl.
Less often substances such as propranolol and benzodiazepines (clonazepam and diazepam) were administered
to control akathisia”
F. Bipolar disorder. (4, 5)
The BAP guidelines on Bipolar Disorder pg. 346 (Goodwin, 2009) state;
“Bipolar patients are probably more likely than patients with schizophrenia to show acute EPS, when treated with
comparable doses of antipsychotics (I, Gao, et al., 2008). Naturalistic studies in schizophrenia suggest that acute
EPS are predictive of subsequent TD (II, Andrew, 1994). It would follow that antipsychotics less likely to induce
acute EPS will be less likely to be associated with TD, but the evidence so far in schizophrenia, while supportive, is
not conclusive (I, Correll, et al., 2004). The trials with atypical antipsychotics show that an anti-manic action can
be achieved without EPS (II, review by Keck,et al., 2000). This is an important clinical message, which should
influence prescribing practice, for all antipsychotics. As in schizophrenia, atypical antipsychotics may be
increasingly preferred to typical antipsychotics because of their established efficacy at doses that do not produce
motor effects.”
Gigante (2012) reviewed the use of LAI antipsychotics in bipolar disorder. He stated in his conclusion;
“The level of evidence about depot antipsychotics in the maintenance treatment of BD is still limited, since there
are only a few large, controlled, randomized trials in the literature. However, it is possible to conclude that FGDA
(FGAs) should not be a first choice in BD patients because of the risk of induction of depression. A possible
exception to this recommendation would include patients who usually do not have depressive episodes and
whose main problem is the recurrence of manic episodes. In addition, the evidence reviewed on LAI risperidone
suggested that this medication is effective as a maintenance treatment in BD. Furthermore, there was no
worsening in depression, although those episodes were not prevented by this medication. LAI risperidone also
seems to be better tolerated than FGDA, mainly in relation to EPS. However, it can cause similar elevations in
prolactin levels as the oral form and may also increase weight. Studies with the new LAI antipsychotics,
olanzapine pamoate and paliperidone palmitate, are needed in BD patients.” This is all consistent with NICE
(2006) recommending SGAs in bipolar disorder.
Maudsley Guidelines;
-On pg. 183 the guidelines state; “The observation that typical antipsychotics are associated with both depression
and tardive dyskinesia in bipolar patients mitigates against their long term use.” Among newer antipsychotics,
olanzapine, risperidone, quetiapine, aripiprazole and asenapine have been most robustly evaluated and are
licenced in the U.K for the treatment of mania.”
-Regarding prophylaxis in Bipolar Disorder, on page 195 Maudsley guidelines recommend olanzapine and
aripirazole as part of first line treatment , and risperidone as part of second line treatment. No FGAs are
recommended.
These SGAs should be effective in preventing manic relapse. Returning to the BAP guidelines pg 367, these SGAs
will not in general prevent depressive relapse (although olanzapine may), but will not increase the likelihood of
depressive relapse as FGAs do Zarate (2004). Aripiprazole is interesting as it has evidence as an adjunctive
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Review Date: October 2022
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treatment for unipolar depression but not bipolar depression. It is a shame that quetiapine is not available in LAI
form as it is effective at preventing relapse of both polarities.
Schizoaffective disorder; There is little research into schizoaffective disorder as its own entity. Concerns about
FGAs contributing to depressed states in schizoaffective disorder are extrapolations from the concerns in bipolar
disorder detailed above. However depression is associated with tardive dyskinesia (Yassa 1984; Rush 1982),
which logically makes FGAs more risky if there is a depressive element to the disorder
Psychotic Depression in non-orally compliant clients - Potential role that LAIs could have in this acute
condition may be added here in due course.
G. Negative/Cognitive symptoms/Anticholinergics.(3, 5,12)
Cognitive Symptoms
Evidence comparing FGAs vs SGAs is mixed. The large European study EUFEST (Davidson, 2009, pg. 679) stated;
“cognitive improvement from a low dose of haloperidol was not significantly different from that of the second
generation antipsychotic drugs. Nevertheless, it is still conceivable that higher doses of haloperidol might exert a
deleterious effect on cognitive performance. Furthermore, these data do not support the contention that
treatment with haloperidol plus anticholinergic drugs is equivalent to treatment with second-generation
antipsychotics”.
With regards to cognitive symptoms BAP guidelines (2010, pg. 23) state “if there are differences between
antipsychotics in improving cognitive performance, they are relatively modest, with none being shown to
normalize cognitive function (Barnes and Joyce, 2001; Davidson et al., 2009). However, there is evidence that the
intrinsic cholinergic activity in antipsychotic drugs and the effects of anticholinergic adjunctive medication
given to tackle EPS can have deleterious effects on cognitive function in patients (Lieberman, 2004; Tracy et al.,
2001; Vinogradov et al., 2009). The need for continued co-prescription of anticholinergic medication should be
regularly reviewed.”
Negative Symptoms.
Leucht (2009) in his meta-analysis found Risperidone to have a significantly better profile for negative
symptoms than first generation antipsychotics. The comparator drugs were mainly chlorpromazine and
haloperidol.
Maudsley guidelines pg. 57 state; “Older antipsychotics have only a small effect against primary negative
symptoms and can cause secondary negative symptoms via EPS” , referencing Leucht (2009) above the guidelines
go on to say “some second generation antipsychotics have been shown to be generally superior to first generation
antipsychotics in the treatment of negative symptoms…..the effect size is small.” However as FGAs can actually
make things worse it could be clinically significant for some.
Direct comparisons between oral Risperidone and Flupentixol (Phillip 2003, Ruhrman 2007) demonstrated little
difference between the two drugs with regards negative symptoms although the use or not of anticholinergic
drugs is not made clear. A comparison between Risperidone and Zuclopenthixol by Fagerlund (2004) identified a
superiority of risperidone regarding cognitive symptoms which was put down to a greater use of anticholinergics
in the zuclopenthixol group. Rubio (2006) showed a superiority for Risperidone LAI vs Zuclopenthixol LAI with
regards to all symptomology (negative and positive) in drugs misusers.
So the evidence shows that SGAs are probably slightly better than FGAs for negative symptoms. Therefore if
negatives symptomology dominates the clinical picture (e.g. rare cases of simple schizophrenia) then an SGA LAI
can be considered.
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H. Hyperprolactinaemia. (8)
FGAs vs Risperidone/Paliperidone. According to Leucht (2013), in oral form, the highest risk lies very
significantly with Risperidone/Palperidone, followed by FGAs. Bazire (pg. 519) states that levels of prolactin are
the same for paliperidone and risperidone. Olanzapine and Aripiprazole are low risk. However Maudsley
Guidelines (2012, pg. 44) states prolactin levels seem to be lower in the LAI form for Risperidone compared to the
oral form. Bazire (pg. 519), quoting (Bai, 2007) found a decrease in prolactin levels of 35% when patients were
changed from oral risperidone to risperidone LAI. Lai (2009) in a small open trial however found levels of prolactin
doubled moving from an FGA LAI to Risperidone LAI.
Unseen effects. Maudsley, pg. 123. States that although often asymptomatic hyperprolactinaemia is
associated with reductions in bone mineral density, suppression of the hypothalamic-pituitary-gonadal axis and a
possible increase in the risk of breast cancer.
Later life Hip fractures. A trial by Howard (2007) found a relationship between hip fractures and prolactin
elevating antipsychotics (mean age 79). Flupentixol had a smaller odds ratio of developing hip fractures compared
to the other prolactin elevating antipsychotics but this may not be significant due to lack of power in the study.
Howard states; “Other mechanisms may also be relevant in causing hip fracture: for example, neuroleptic
medications are known to cause sedation, orthostatic hypotension and extrapyramidal side-effects, which may
predispose some patients on these treatments to falls (Misra et al, 2004).”Rates of hip fracture were similar in the
Risperidone (small confidence intervals as small sample) and Haloperidol group.
A larger trial of nursing home patients (Huybrechts, 2012) says findings suggest but do not confirm that FGA LAIs
have a greater risk of hip fracture than SGA LAIs. However surprisingly olanzapine and aripiprazole were
approximately on a par with risperidone.
KEY UNCERTAINTY. A full literature search has not been done, but above shows that regarding hip fractures in
the elderly the relationship to prolactin elevating drugs is uncertain. It may come down to length of time on the
drug.
Breast Cancer. Wang (2002) in a large retrospective case control study found a relative risk of developing
breast cancer for dopamine antagonists (FGAs plus risperidone and clozapine as a cohort) was 1.16 (CI 1.07-1.26).
He concluded that because these were small risks especially in absolute terms it should not lead to changes in
treatment strategies but instead follow up investigations. Harvey (2008) looking at evidence from rodent,
epidemiology, patient studies involving endocrine evaluation, and molecular biology in human cells studies was
more concerned. See Maudsley recommendations below
Maudsley guidelines pg. 124 states that prolactin elevating drugs should if possible be avoided in the under 25s
(before peak bone mass), in patients with osteoporosis and patients with history of hormone dependent breast
cancer. Maudsley also states “long term use should probably be avoided in young women given the possibility of
increased breast cancer and the known risk of decreased bone mineral density”.
However their use may be unavoidable so ensure adequate monitoring of prolactin levels.
Low dose aripiprazole is an effective adjunct treatment of hyperprolacinaemia but if someone is on a depot it
suggests they are not good at taking oral medications. Better to be on aripiprazole LAI if effective and tolerated.
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Review Date: October 2022
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I. First episodes (10)
Avoiding side effects
-Bazire (2014, p.g172) referring to first episode psychosis states; “Patient choice considered a high priority. A
meta-analysis has concluded that there is no difference in efficacy between SGAs and FGAs in early psychosis but
there is a significant difference in (predictable) ADRs (adverse drug reactions) (Crossley 2010)…consider what
the patient prefers .Weight gain is the most unpopular side- effect and its impact on the user must not be
trivialised and is 3-4 times more common in the younger, first episode patients compared to older chronic
patients (Alvarez-Jiménez 2008)”
-Maudsley (2012, pg. 134) states; “Risk of diabetes is increased to a much greater extent in younger adults than
in the elderly…..first episode patients seem particularly prone to the development of diabetes when given a
variety of antipsychotics.”
-EUFEST Trial. Khan (2008) found that haloperidol was more poorly tolerated than the SGAs it was compared
against.
-Bazire (pg. 172) goes on to state “Minimise obvious ADRs that may make a person appear more abnormal, e.g
EPSE and which reduce compliance with engagement (Amminger 2003)”
-British association of psychopharmacology schizophrenia guidelines (Barnes, 2011. Pg. 5) state; “There is a
biological sensitivity to such medication in the early stages of the illness which applies to both the therapeutic
effects and the adverse effects. Thus, there is a consensus that clinicians should use the lowest recommended
dosage of an antipsychotic when initiating medication. ….Minimizing adverse effects, such as extrapyramidal and
aversive subjective side effects, is particularly important at this stage given that they can be a short-term
disincentive for medication adherence and have an impact on attitudes to drug treatment and mental
healthcare over the longer term (Perkins et al., 2008; Robinsonet al., 2002).”
It is also worthy of note that Dilip (1999) found that for over 45s starting FGAs they were more likely to develop
tardive dyskinesia if they had been previously exposed for more than 28 days(range 28 days to 5 years, average
exposure 4 months) to FGAs. So what patients are put on early could have an impact further down the line.
Ensuring successful treatment
Successful first episode schizophrenia (FES) treatment is crucial to minimize social and vocational deterioration
(Robinson, 2005). A more recent meta-analysis of the data disagrees with Crossley (2010) that FGAs and SGAs are
equally effective. Jian-Ping Zhang (2013) states; “in first episode schizophrenia, olanzapine, amisulpride and, less
so, risperidone and quetiapine showed superior efficacy, greater treatment persistence and less EPS than FGAs.
However, weight increase with olanzapine, risperidone and clozapine and metabolic changes with olanzapine
were greater.” It is not surprising in this trial that weight gain was greater with risperidone compared to FGAs as
the comparator drugs used were haloperidol and Molindone (now discontinued) which is known to cause weight
loss.
His summary is as follows “Overall, risperidone appears to be reasonably efficacious and is associated with
relatively benign side effects, so it should be considered as a first line therapy for first-episode schizophrenia.”
However he has not considered the potential unseen side effects with hyperprolactinaemia seen with
risperidone. However he does say, “studies with aripiprazole and newer SGAs that generally have less metabolic
liability (De Hert et al.,2012) are clearly needed”, he goes on, “SGAs were significantly superior for negative
symptoms, global cognition and long-term relapse outcomes compared to FGAs.”
Bazire (2014, pg. 173) gives Aripiprazole oral a responder rate of 79% compared to 82% for olanzapine for first
episode schizophrenia (see also Takahashi 2009, Lee 2010). This is more equal than their relative efficacies in
other patient groups (Leucht 2013). This makes first episode schizophrenia a good time to try aripiprazole.
Paliperidone may be preferred in highly agitated states as it is less likely than aripiprazole to cause akathisia and
has sedating properties, however beware hyperprolatinaemia in the young especially women. Looking at late
onset (40 years old) schizophrenia, Denning (2013, pg. 611) recommends SGAs because of propensity for EPSE
and T.D at that age but individual drug cardiac risk needs consideration.
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J. Deltoid Injections (11)
Deltoid administration of paliperidone and aripiprazole LAIs are licenced. Deltoid administration of FGA LAIs, and
olanzapine LAI is not licenced. If ever deemed appropriate no more than 2ml volume should be administered and
low doses should be used as uptake from the deltoid is faster than gluteal. THIS WOULD BE OFF LICENCE USE
Olanzapine LAI and Fluphenazine LAI should probably never be given in the deltoid. Also consider the lateral thigh
as Flupentixol and Zuclopenthixol are licenced for administration at that site.
K. Very high Risk patients (14)
With regards to this group it is recommended that clinical indication rather than cost of the medication is a
priority. Often these clients have elements of personality disorder or their primary diagnosis may be personality
disorder.
Schizophrenia and aggression
BAP guidelines on schizophrenia (2010) concluded that there is little difference between antipsychotics with
regards to effect on aggression except that clozapine is superior. They do state that outcomes for LAI medication
compared to oral are significantly better.
Since then a review by Citrome (2011) concluded, “For patients with schizophrenia and persistent aggressive
behaviour, clozapine is recommended both for its superior antipsychotic effect and also its specific anti-hostility
effect. The other second-generation antipsychotics may also have advantages over older agents such as
haloperidol in terms of reduction of hostility, but their main distinguishing feature is their lower propensity to
be associated with extrapyramidal adverse effects, including akathisia.” The best evidence for superiority
seems to be for olanzapine followed by risperidone. This may in part reflect the high level of overall clinical
efficacy risperidone and olanzapine have demonstrated in recent meta-analyses (Leucht 2013)
There is a significant amount of evidence to link akathisia with violence (egg Leong 2003). Aripiprazole LAI with its
risk of akathisia relative to other SGAs, and lack of sedative properties should be used with caution. FGAs because
of their even greater liability to cause akathisia should also be used with caution.
Personality disorder.
The use of antipsychotics in those with a diagnosis of personality disorder without co-morbidity is controversial
and should be carefully considered as it could make things worse. Even if oral antipsychotics are occasionally used
in this client group it will be only in exceptional circumstances that an LAI is used.
Borderline Personality Disorder. NICE guidelines on Borderline Personality disorder were published in
2009. In 2010 (Klaus) a Cochrane review was published on Borderline Personality disorder and psychotropics.
They commented on the NICE conclusions stating;
“It is of note that this comprehensive guideline (NICE) recognises evidence for the reduction of specific symptoms
with some pharmacological treatments, but that the final recommendations do not reflect this evidence.
Although more robust findings would certainly be desirable, and we appreciate concerns related to giving strong
recommendations, we suggest considering a reassessment of these recommendations, as there actually is
encouraging evidence of the effectiveness of drug treatment for individual symptoms of borderline personality
disorder.”
Klaus (2010) found some evidence for two FGAs; “The comparisons of first-generation antipsychotics (FGAs) with
placebo yielded significant effects for haloperidol in the reduction of anger and flupentixol decanoate in the
reduction of suicidal behaviour.” Flupentixol though should probably not be used with agitated/aggressive
patients. Klaus found that aripiprazole was twice as effective for anger compared to haloperidol. Olanzapine was
also effective in reducing anger. Overall Klaus states in the abstract results (Pg. 4) “Most beneficial effects were
found for the mood stabilisers topiramate, lamotrigine and valproate semisodium, and the second-generation
antipsychotics aripiprazole and olanzapine… the current evidence from randomised controlled trials suggests that
drug treatment, especially with mood stabilisers and second-generation antipsychotics, may be effective for
treating a number of core symptoms and associated psychopathology, but the evidence does not currently
support effectiveness for overall severity of borderline personality disorder. Pharmacotherapy should therefore
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be targeted at specific symptoms.” Their evidence comes from the use of oral aripiprazole and olanzapine.
Caution should be taken as they identified that placebo was superior to olanzapine in most trials measuring
suicidal thought and self-harm. Aripiprazole seems to be emerging as a treatment of choice in BPD however
again caution should still be taken as it can cause akathisia without a sedative effect (however there less risk of
akathisia in a P.D population).
With regards to risperidone there have been a couple of open label trials of Risperidone LAI in the treatment of
BPD showing efficacy, but without a comparator group. One of them by Carrasco concluded “Symptom reduction
was statistically significant for aggression scores”. Bellino in a 2012 review stated; “Concerning risperidone and its
metabolite paliperidone, clinical data are sparse and derive from few case reports and open investigations on
small samples”. A review by Vita (2011) stated “antipsychotics, may be effective for treating affective
dysregulation and impulsive-behavioural dyscontrol. Antipsychotics were also effective in reducing cognitiveperceptual symptoms”
Anti-social personality disorder. Evidence for any antipsychotics is even sparser in the treatment of ASPD.
Volm (2010) in his Cochrane review concludes, “very little research is carried out with regards to interventions in
this patient group and subsequently the evidence base to support any interventions is extremely limited”. NICE
(2013) say antipsychotics should not be routinely used.
Overall the use of antipsychotics in personality disorders has poor evidence base that may improve in time.
Caution should be taken as akathisia can be precipitated. Regarding personality disordered clients who are
threat to others it is advisable to discuss with specialist forensic services.
L. Cardiac risks and Sudden Cardiac Death (SCD)-see also section on weight and
metabolic syndrome. (3, 6, 9)
QTc prolongation, tachycardia and orthostatic hypotension risk is particularly an issue when using a LAI due to the
long duration of action, and greater difficulty controlling dose. Risk of Sudden Cardiac death is dose related for
many drugs. Great care is needed especially if the tolerability of the drug is unknown.
This section consists of;
1. Non metabolic syndrome cardiac considerations before starting LAI (QTc,Orthostatic
hypotension/tachycardia)
2. Anticholinergic effects.
3. Quantifying overall risk of antipsychotics/population based studies.
4. Evidence to support relative risks of each drug.
5. Relationships between mental disorder, SCD ischaemic heart disease, and age
6. All-cause mortality data.
1. Things to look out for before starting LAI
Regarding QT specifically Bazire (pg. 249) gives the following as risk factors with antipsychotics, so to use the
lowest risk drug possible in the following scenarios if possible;
- Other meds increasing QTC (Bazire pg. 248)
- Underlying cardiac disease. E.g. IHD, heart failure, cardiomyopathy
- Bradycardia or second or third degree heart block.
- Personal or F.H of QTc prolongation, vent arrhythmias or torsades de pointes.
- Severe renal or hepatic impairment.
- Elderly or malnourished.
- History of heavy alcohol consumption or substance misuse
- Electrolyte imbalance especially hypokalaemia and hypomagnesia
- Undergoing restraining and/or severe stress
- Slow drug metabolisers
- Female gender.
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Dyspnoea, syncope, palpitations are some of many symptoms that could alert the clinician to the above
undiagnosed problems.
Age is another factor associated with QTc prolongation.
The thiamine and Magnesium deficiency found in the undernourished and alcoholics can increase QTc.
Tachycardia and Orthostatic Hypotension.
Tachycardia. This is often related to orthostatic hypotension or anti-cholinergic effects. (Drugs & Therapy
Perspectives, 2012, O’ Brien 2003)
Orthostatic Hypotension. This is more evident in elderly patients often due to alpha 1 blockade with
antipsychotics. Younger clients are more able to muster a reflex tachycardia to compensate (Drug and therapy
perspectives, 2012). If the client has them try to avoid antipsychotics or choose carefully. Below is given some
disorders that can cause orthostatic hypotension.
Autonomic dysfunction
Dehydration
Diabetes mellitus
Anorexia
Alcohol dependence
Vomiting
Parkinson’s disease
Diarrhoea
Multiple system atrophy
Catatonia
Pure autonomic failure
Febrile illness
Other drugs
Other Disorders to be wary of if there is a risk of precipitating Orthostatic hypotension;
According to Gugger (2011) “Complications of orthostatic hypotension include syncope, transient ischaemic
attack, stroke, myocardial infarction and death.” Therefore one would be wary if a client has a history of these
highlighted.
Congestive heart failure and Angina will also be vulnerable to hypotension.
KEY UNCERTAINTLY-Length of time it takes for body to adapt to drug and hypotension to diminish (if at all)
Arrhythmias.
Bazire, pg. 249, states; “Avoid phenothiazines, butyrophenones and pimozide. Sulpiride and olanzapine seem
to be of low risk.” CONSULT A CARDIOLOGIST
Hypertension
According to the Maudsley pg. 123, there are a small number of yellow card reports of aripiprazole, olanzapine
and risperidone causing hypertension. This is rare and they are not contraindicated in hypertension.
2. The Confusion over Anti-cholinergic effects.
O’Brien states “Psychotropic drugs possessing anti-muscarinic and anti-cholinergic effects (e.g. all low-potency
typical antipsychotics; some atypical antipsychotics…) cause sinus tachycardia which, in otherwise healthy
individuals, rarely leads to symptoms and usually remits over time.” He adds that medications with
anticholinergic effect can cause reduction in normal heart rate variability. He goes on “Reduced heart rate
variability post-myocardial infarction carries a poor prognosis of increased cardiac mortality and sudden death
from unopposed sympathetic arrhythmogenic influences (Bigger et al, 1996)……Strategies for increasing heart
rate variability would therefore appear desirable, and these include physical exercise, b-blockade and low-dose
anti-cholinergic hyoscine hydrobromide (scopolamine) therapy, which paradoxically increases vagal
parasympathetic activity (Bigger et al, 1996). This paradoxical finding might explain the poorer cardiac outcome
in patients with chronic schizophrenia who are not co-treated with anticholinergic medication (Waddington et
al, 1998).” Waddington (1998) had found in a group of long term institutionalised clients (average age 63) on
FGAs that anticholinergic use may be a protective factor against sudden cardiac death. (relative risk 3.33, 95%
CI 0.99-11.11; P : 0.05). This is an isolated result on an unusual population who may have been on very high
doses of antipsychotics and has not been investigated elsewhere. On balance anticholinergic effects of
antipsychotics are likely to have a negative impact on cardiac function, for example tachycardia precipitating
angina. Additionally anti-cholinergic effects are associated with significant other morbidity. Gerritson states, “A
French study of more than 9000 dementia-free individuals >65 years old found that anti-cholinergics were
commonly prescribed and associated with executive function, memory and processing speed deficits. Elevated
anticholinergic activity also contributes to weakness, fatigue, cognitive and psychomotor slowing, and falls.”
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3. Quantifying risk of antipsychotics.
Ray (2009). In a cohort of clients aged 30-74 found that the rate of sudden cardiac death is approximately
doubled amongst those on antipsychotics independent of mental illness. He states there was a significant
dose response relationship. Previous users did not have significantly different risk compared to people who
had never used antipsychotics. He also asserted that metabolic syndrome was not a factor as he re-analysed
the data on those who had had less than 365 days of the antipsychotic and found it made no difference to the
figures (although it is worth noting that metabolic syndrome often develops in the first 3 months on an
antipsychotic). Schneeweiss (2009) interprets Ray’s figures and states “The incidence rate reported by Ray
was… 2.9 events per 1000 patient-years. Among patients given higher doses, the rate was 3.3 events per
1000.” Considering Ray states antipsychotics double the natural rate; about 1.5 of 2.9 deaths per 1000 patient
treatment years due to sudden cardiac death could be put down to the antipsychotic. Trials comparing FGA’s
vs SGAs are not that helpful as we want to know about individual drugs.
Risks of specific antipsychotics in population based studies.
A review of neuroleptics and arrhythmias has just been published Fanou (March 2014). The review sourced a
lot of material from regulatory agencies. She identifies 3 antipsychotics (aripiprazole, olanzapine and
zuclopenthixol) as- “Class A- A drug considered to be without any risk of QT prolongation or TdP” and suggests
they don’t need ECG monitoring. However QTc prolongation evidence is poor for a lot of drugs and it seems
considered population studies of Sudden Cardiac death were not considered. It seems wiser to follow
Maudsley guidelines advice pg. 120 “In the absence of conclusive data, assume all antipsychotics are linked to
sudden cardiac death”.
Leonard (2013) states; “putative markers of risk, such as a drug’s ability to prolong the QT interval or inhibit
cardiac ion channel currents, may not be reliable predictors of arrhythmogenicity in clinical use [4].
Therefore, outcome studies in clinical populations are crucial to quantify risk and inform our understanding
of the aetiology of drug-induced arrhythmias.” Relevant population studies are mentioned under relevant
drugs.
4. Cardiac information for each LAI from various sources. Evidence is at
times conflicting.
See Maudsley pg. 151 and Bazire pg. 202 for relative hypotension and anticholinergic effects. See sections on
cardiac risk in Bazire 248-252. Individualise the antipsychotic side effect profile to the client’s cardiac needs.
The below assessments are based mostly on oral medications. With regard to LAIs one could speculate that
LAIs with short half-lives and fast times to peak may cause more unpredictable cardiac effects, see table 2.
There is no clinical evidence to support this idea.
Haloperidol
Hypotension.
Maudsley “Low”, Bazire “Mild”
Anticholinergic.
Maudsley “Low” Bazire “moderate.”
QTc prolongation. Maudsley “High” Bazire “mild”. Did well in Leucht (2013) meta-analysis.
Based on the above one may expect it to be quite safe however;
Fanoe (2014) Arrhythmia rating. Class B*-A drug with pronounced QT prolongation, documented
cases of TdP, or other serious arrhythmias
Bazire cardiac risk ratings pg248.”high risk”
Bazire cardiac risk rating pg. 201. “medium”
Population based trials. Regarding SCD Ray (2001) found it did well compared to other FGAs. Strauss (2004)
then concluded it was the most risky in his analysis of the FGAs. Ray (2009) then found it was less risky than
risperidone (not significant). This was reversed again by Leonard (2013) in the largest population study to date,
with haloperidol risk as high as 6.7 SCD per 1000 treatment years.
Comment. For general cardiac risk Bazire warns against its use (pg. 245) in arrhythmias, but suggests it is lower
risk than phenothiazines if there is history of MI. Based on population data it seems reasonable to suspect
Haloperidol to have cardio-toxic potential independent of QTc prolonging potential. (Leonard 2013, Strauss
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2004)
Flupentixol
Hypotension.
Maudsley “Low”, Bazire “Little/minimal”
Anticholinergic.
Maudsley “moderate” Bazire “moderate.”
QTc prolongation. Maudsley “Low” Bazire “mild”. Not in Leucht meta-analysis
Fanoe (2014) Arrhythmia rating. B- A drug with a propensity of inducing QT prolongation
Bazire cardiac risk ratings pg248.”moderate”
Bazire cardiac risk rating pg. 201. “little or minimal”
Population bases trials. Most population trials did not identify Thioxanthenes as a group to analyse alone.
Strauss (2004) did but the numbers are too low with huge confidence intervals to guide us much.
Comment. A concern is lack of population based data.
Zuclopenthixol.
Hypotension.
Maudsley “Low”, Bazire “Mild/transient” (Mild/transient is more than little/minimal for
Bazire)
Anticholinergic.
Maudsley “moderate” Bazire “marked effect.”
QTc prolongation. Maudsley “Not Known” Bazire “none”. Not in Leucht meta-analysis
Fanoe (2014) Arrhythmia rating. Class A -A drug considered to be without any risk of QT prolongation or TdP
Bazire cardiac risk ratings pg248.”moderate”
Bazire cardiac risk rating pg. 201. “mild/transient”
Population bases trials. Most population trials did not identify Thioxanthenes as a group to analyse alone.
Strauss (2004) did but the numbers are too low with huge confidence intervals to guide us much.
Comment. On paper an OK choice. It may have a bit more anticholinergic and hypotensive potential than
Flupentixol and perhaps less is known of its QTc potential, but it gets a good arrhythmia rating from Fanou. The
main concern is lack of population based SCD data. May be the FGA of choice in cardiac disease.
Fluphenazine NO LONGER AVAILABLE
Hypotension.
Maudsley “Low”, Bazire “Mild/transient”
Anticholinergic.
Maudsley “moderate” Bazire “moderate.”
QTc prolongation. Maudsley “low” Bazire “mild”. Not in Leucht meta-analysis
Fanoe (2014) Arrhythmia rating. Not given but perphenazine rated A.
Bazire cardiac risk ratings pg248. Not given but phenothiazines given “moderate”. Bazire recommends
avoiding phenothiazines in angina, arrhythmias, congestive heart failure and myocardial infarction. This
probably applies more to the lower potency phenothiazines.
Bazire cardiac risk rating pg. 201. ”moderate”
Population bases trials. Phenothiazines as a group have generally performed badly (e.g. Honkola, 2011). In
recent Leonard trial (2013) Fluphenazine performed quite well. Perphenazine did even better
Comment. Probably overall less risky than pipotiazine but has high risk of EPSE which can contribute to
morbidity in other ways.
Risperidone.
Hypotension.
Maudsley “Moderate”, Bazire “Mild/Transient”
Anticholinergic.
Maudsley “low” Bazire “Little/minimal.”
QTc prolongation. Maudsley “low” Bazire “mild”. Greater effect size than haloperidol in Leucht meta-analysis
Fanoe (2014) Arrhythmia rating. B- A drug with a propensity of inducing QT prolongation
Bazire cardiac risk ratings pg248. “moderate”. Bazire pg. 249 recommends avoiding Risperidone in angina and
congestive heart failure, probably reflecting hypotensive effects.
Bazire cardiac risk rating pg. 201. “Little/minimal”
Population based trials. Hennesey found Risperidone to be more risky than haloperidol (significant). Ray
(2009) found Risperidone had a higher risk of SCD than haloperidol (not significant). However Leonard (2013)
found the complete opposite. There was an inverse relationship of dose to risk with Risperidone in the
Hennesey (2002) trial so it may reflect selection bias with risperidone being used in the more frail.
Comment. Conflicting evidence.
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Paliperidone
Hypotension.
Maudsley “Moderate”, Bazire “Mild/Transient”
Anticholinergic.
Maudsley “low” Bazire “Little/minimal.”
QTc prolongation. Maudsley “No effect” Bazire “No effect”. Smaller effect size than haloperidol in Leucht
meta-analysis, but not statistically significant.
Fanoe (2014) Arrhythmia rating. B- A drug with a propensity of inducing QT prolongation
Bazire cardiac risk ratings pg248. “moderate”. Bazire pg. 249 recommends avoiding Risperidone in angina and
congestive heart failure, probably reflecting hypotensive effects. This would apply to paliperidone too in theory
Bazire cardiac risk rating pg. 201. “Little/minimal”
Population based trials. See risperidone. No trials specifically on paliperidone. Probably similar
Comment. Conflicting evidence. Cautious interpretation of possible difference between QTc for Paliperidone
and Risperidone as there is no scientific rationale for a difference.
Olanzapine
Hypotension.
Maudsley “low”, Bazire “little/minimal”
Anticholinergic.
Maudsley “low” Bazire “Little/minimal.”
QTc prolongation. Maudsley “low” Bazire “mild”. Slightly greater effect size than haloperidol in Leucht metaanalysis
Fanoe (2014) Arrhythmia rating. Class A -A drug considered to be without any risk of QT prolongation or TdP
Bazire cardiac risk ratings pg. 248. “moderate”.
Bazire cardiac risk rating pg. 201. “Little/minimal”
Population based trials. Performed averagely in the Ray (2009) and Leonard (2013) trial
Comment. On paper a good choice and in practice OK. Beware metabolic syndrome, which will be associated
with various wider ranging mortality.
Aripiprazole
Hypotension.
Maudsley “Very low”, Bazire “Little/minimal”
Anticholinergic.
Maudsley “Very low” Bazire “Little/minimal.”
QTc prolongation. Maudsley “No effect” Bazire “mild”. Almost 0 effect size in Leucht meta-analysis. Chung
(2011) did a meta-analysis of QTc in the second generation antipsychotics and found, “Aripiprazole was the
only SGA associated with both statistically significant lower risk and mean change in QTBc”.
Fanoe (2014) Arrhythmia rating. Class A -A drug considered to be without any risk of QT prolongation or TdP
Bazire cardiac risk ratings pg248. “moderate”.
Bazire cardiac risk rating pg. 201. “Mild transient”
Population based trials. Ray (2009b) responded to correspondence asking why in his 2009 population study he
had not specifically looked at aripiprazole and ziprasidone. He stated that too few people in the population had
been on aripiprazole to give enough power and stated “We believe that these particular atypical antipsychotic
drugs should not be considered free of risk for sudden cardiac death until further data become available.”
Subsequent to that Leonard (2013) looked at a medicare database of 30-75 year olds (the largest population
trial to date,) and found aripiprazole had a crude sudden cardiac death rate of 0.6 per 1000 patient treatment
years compared to a rate of 3.4 with olanzapine, 3.8 with risperidone, and 6.7 with haloperidol and
chlorpromazine. Leonard’s result needs repeating in other trials before we get carried away, as confidence
intervals were wide, but it makes sense based on aripiprazole’s side effect profile. Also we have to be cautious
regarding aripiprazole LAI as like the FGA LAIs it has higher rates of EPSE than in its oral form, perhaps
suggesting slightly greater toxicity in this form.
Comment. Even with aripiprazole there are now warnings in the SPC of orthostatic hypotension, and QTc
prolongation as a possibility. Raschi (2011) suggests QT shortening can also be a risk and is a rare thing to look
out for with aripiprazole. We know that cardiac toxicity does not necessarily correlate with hypotensive,
anticholinergic and QTc affects, but with aripiprazole we are starting to get population evidence to back up its
theoretical advantages. Bazires “cardiac” ratings on page 201 seem to suggest that Olanzapine, Risperidone,
paliperidone, and flupentixol have a slightly better overall cardiac rating, and zuclopenthixol the same
compared to aripiprazole. But he rates them all the same on page 248. He has not however considered the
Leonard paper, and his ratings are somewhat inconsistent. On current evidence aripiprazole seems to have
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the best overall cardiac profile of all antipsychotics.
5. The confusing Relationships Between Antipsychotics, SCD, Ischaemic Heart
Disease (IHD)/Coronary Heart Disease(CHD), Severe mental illness and Age
Taking into account the following papers (Fanoe 2014, Osborn 2007, Ray 2009, Murray Thomas 2013,
American Heart Association 2010, Scott 2012), one can most sensibly interpret that;
1. According to Ray (2009), for a population average age of 46 the relative risk of SCD for those on
antipsychotics vs those who are not is approximately 2.
2. We do not know if the relative risks change with age (Murray-Thomas 2013)
3. However with increasing age the absolute risk of SCD increases in the whole population probably
making antipsychotic use very significantly more risky overall, the older you get. ( Ray 2001, Ray 2009,
Murray-Thomas 2013)
4. Osborn (2007) found, hazard ratios for CHD mortality in people with SMI compared with age matched
controls were; 3.22 (95% [CI], 1.99-5.21) for people 18 through 49 years old; 1.86 (95% CI, 1.63-2.12)
for those 50 through 75 years old; and 1.05 (95% CI, 0.92-1.19) for those older than 75 years.
5. Osborn’s results may reflect a healthy survivor phenomenon and or demonstrate an attenuation of
metabolic syndrome with age.
6. However as CHD/IHD risk increases dramatically with age in the general population there will still be an
absolute increase in CHD/IHD risk with age in the SMI population. (American heart association)
7. CHD/IHD are a risk factor for SCD so antipsychotics should be used with caution in older age.
8. The older heart is probably more vulnerable to direct cardio-toxic effects of antipsychotics through
normal ageing (See Medline plus)
9. As there is a relatively high rate of IHD/CHD in younger adults with SMI compared to the general
population, and it is often undiagnosed and untreated (Scott, 2012), it should not be assumed they do
not have IHD/CHD
KEY UNCERTAINTY- Most of the literature on SCD has been looked at but there is more literature on
IHD/CHD in mental illness that has not been extensively reviewed and nor has how antipsychotics
may effect a non IHD ageing heart.
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6. All Cause Deaths.
The literature on all cause deaths comparing FGAs and SGAs is somewhat inconclusive and not always that
helpful as all FGA’s and SGAs are often grouped together and compared against each other telling us little
about individual drugs. Papers considered are; Khan (2013), Murray-Thomas (2013), Leonard (2013), Dean
2009, Wang (2005), Saha (2007), Enger (2004) and Dean (2009). Wang and Murray Jones point to an excess
mortality with A.Ps particularly FGAs, and it being most marked early on in treatment perhaps up to first 2
years of use and especially in the first 40 days, so monitoring is extremely important during that period. A lot
of the FGAs in the trial were not the ones we are interested in here. Leonard’s (2013) paper is more helpful as
it compares the antipsychotics individually. On comparing antipsychotics he found aripiprazole had the lowest
rate of all cause deaths and the confidence intervals were quite narrow. It adds weight to the idea that
avoiding side effects identified in table 1 by prescribing aripiprazole, could lead, to decreased mortality as well
as morbidity.
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M. Aripiprazole Pharmacodynamics.
As stated by Mallikaarjun (2013) “Simulation modelling also indicated that the maintenance of therapeutic
concentrations observed with oral aripiprazole (10-30mg) was best achieved by supplementing the initial
aripiprazole once monthly injection with oral aripiprazole (10mg/day) for the first 14 days while aripiprazole
concentrations derived from the once monthy injection reached therapeutic levels.” Then on page 285 “A 2-week
oral supplementation regimen was used to ensure a smooth transition between the oral and extended-release
formulations while concentrations of aripiprazole derived from the once-monthly injection reached therapeutic
levels. This 2-week overlap was based on an exploratory analysis of single-dose aripiprazole once-monthly and
oral steady-state studies.”
Taken from Mallikaarjun (2013)
We can see from the graphs that for clients already stabilised on 10mg once daily, and continuing orals for 2
weeks after the LAI on day one, there is a boost to levels on day 1, but it seems once the orals are stopped 2
weeks later the levels drop off again. In oral form the half-life of dehydroxo-aripiprazole (active metabolite) is
approx. 4 days. It is hard to know what the pharmacodynamics would be for someone not already stabilised on
oral aripiprazole and not able to have the 2 weeks cross over. Considering the half life of oral aripirazole it seems
logical to think it would take non orally compliant clients about 2 ½ weeks to start to correlate fully with the
pharmacodynamic profile above. This does not mean therapeutic levels are not reached before 2 ½ weeks with
the LAI alone as it peaks at 2 weeks.
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Appendix 1. (8 ,13) Older adult population (>65). Schizophrenia in old age, and Very
Late Onset Schizophrenia like psychosis (Without dementia)
FGA vs SGA
SGAs and FGAs are associated with significantly increased mortality in Dementia. Trust guidelines (PG14) advise
against the use of FGAs in this population. Late onset schizophrenia (LOS) is first onset >40yrs old. Very late onset
schizophrenia like psychosis (VLOSLP) is for those >60yrs old. Little research has been done on the elderly
schizophrenia non-dementia population. For the LOS and VLOSLP cohort Denning (2013) in the “Oxford textbook
of old age psychiatry states; “Atypical antipsychotics are now favoured mainly because of the propensity of first
generation to induce extrapyramidal symptoms and tardive dyskinesia to which older individuals are more
prone.” Alexoupolos (2014) also recommends SGAs. Therefore use of an SGA could be justified on these grounds
alone.
Wang (2005) compared FGAs vs SGAs (any diagnosis) in the over 65 population and found a relative risk of allcause mortality in favour of SGAs. In demented patients the relative risk was 1.29 (1.15–1.45) and non-demented
patients 1.45 (1.30–1.63). These results are worth bearing in mind, but the FGA group included drugs such as
haloperidol, fluphenazine, but also thioridazine and chlorpromazine, and not flupentixol, zuclopenthixol or
pipotiazine, so of limited help regarding our LAIs. Wang found the risk with FGAs is lessened with lower doses
(but still not quite equal with SGAs regular doses).
So although we are certainly leaning in favour of SGAs more individualised assessment should take place. Essali’s
(2012) meta-analysis of LOS/VLOSLP concluded “Until they (more studies) are undertaken, people with late-onset
schizophrenia will be treated by doctors using clinical judgement and habit to guide prescribing.” Information on
some trials and reviews for individual SGA LAIs is give below for each SGA LAI. There is a lack of RCTs explaining
Essali’s conclusion. However we do have side effect data we can extrapolate from the general adult population.
Perhaps also extrapolations could be made from the dementia population. DUE TO CONSTRAINTS OF TIME AND
SPACE A REVIEW OF EVIDENCE FROM DEMENTIA POPULATIONS IS NOT INCLUDED HERE - Consult with an older
adult psychiatrist for more advice.
Ability to administer small doses of the medication is also a factor to consider
Side Effects To Consider.
All potential side effects should also be considered and the most appropriate drug used. The elderly are
vulnerable to sudden cardiac death (Ray 2009, Murray-Thomas 2013) mainly due to increased rates of IHD but
other additional factors such as prolonging of the QTc with age, or vulnerability to arrhythmias in general may
also be involved. The elderly are also more vulnerable to other antipsychotic side effects. Especially consider each
individual’s particular vulnerability to, anticholinergic effects, hypotension potential, cardiac side effects, and
over sedation. Also consider inhibition of hepatic enzymes and half-life of the drug. This list is not exhaustive.
Maudsley Guidelines (2012, pg. 151) and Bazire (2014, pg. 201), give helpful comparative tables of drug side
effects.
Please see BOX H on hyperprolactinaemia for risks of prolactin elevating drugs in the elderly.
Please see BOX G for morbidity associated with anticholinergic effects.
Please see BOX L for sudden cardiac death risk and how age relates to this and IHD.
Please see BOX D for increasing T.D risk with age.
KEY UNCERTAINTY- Maudsley (pg. 511) quoting Trifiro (2009) states metabolic syndrome tends to be attenuated
with advancing age and in elderly patients with dementia. I found one paper to back up that statement;
Lieberman (2004) demonstrates that the diabetes risk with antipsychotics drops off a bit after 70 years of age.
Venous Thrombo-embolism risk.
There has not been enough research on relative risks of antipsychotic on DVT and venous thromboembolism risk
in the LAIs we are interested in here. It seems to be misleading to consider there to be an FGA/SGA divide. For
those interested Parker (2010, table 5) gives some relative risks that suggest that risperidone and olanzapine are
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safer than haloperidol but whether the differences are significant is not stated. Most of the medications we are
interested in here have not been looked at. THIS AREA REMAINS A KEY UNCERTAINTY.
FGAs.
With regards the FGA LAIs there is clear guidance in the BNF on recommended doses in the elderly, and small
doses can easily be drawn up and administered. EPSEs can lead to falls and subsequent mortality.
Regarding FGA LAIs Howard (1992) found; “Despite their better treatment response rate, patients prescribed
depot medication received on average a lower daily dose in chlorpromazine equivalents than those prescribed
oral medication. Improved compliance, greater clinical efficacy and a reduction in the dose of neuroleptic
medication administered are all good reasons to commence treatment of late paraphrenia with a depot
antipsychotic medication.” Reeves (2002) did not find the same comparative benefit in treatment response with
LAIs.
KEY UNCERTAINTY.
Oxidative stress may be associated with dementia and tardive dyskinesia. E.g. Khafila (2004), states that
risperidone doesn’t but zuclopenthixol does causes oxidative stress in rats. Martins (2008) suggests that
haloperidol causes similar oxidative stress bit aripiprazole and olanzapine do not. Where these type of studies
will lead clinically at this point in time is uncertain.
Risperidone/Paliperidone LAI
With regards to risperidone in oral form Jacoby (2008, pg. 623) states “When compared to treatment with
traditional neuroleptics in open label studies risperidone has been shown to improve cognitive functioning and to
result in a significantly lower cumulative incidence of tardive dyskinesia.” Jeste (2000) found that for oral
risperidone the one year rate of persistent tardive dyskinesia in a group of dementia clients was 2.6%.
There are a couple of open label trials without control groups for the use of risperidone LAI in this age group.
Palperidone has not been trialled in this age group. In a 6 month open label switch trial for over 65’s Kissling
(2007) states “Conversion to RLAI resulted in significant improvements in movement disorder severity, psychiatric
symptoms, functional status and patient satisfaction.”
Inoue Y. (2010). Switched 15 patients from oral antipsychotic or Haloperidol LAI, to Risperidone LAI and
concluded “These results demonstrated that RLAI is clinically effective in elderly schizophrenia patients, and
suggest that RLAI may afford superior efficacy and safety, since, for example, no extrapyramidal symptom
exacerbation, weight gain, lipid abnormalities, or hyperprolactinemia was seen, and since both clinical efficacy
and adverse reactions were unaffected by either age or dose.”
Watch out for orthostatic hypotension. See BOX L
There is no mention of this age group in the BNF (2014) or SPC for Risperidone LAI. For paliperidone LAI the SPC
states “Efficacy and safety in elderly > 65 years have not been established.” The SPCs for dosing for Risperidone,
Xeplion and Trevicta give contradictory advice, regarding dose and renal function in the elderly. Dose adjustment
may be necessary as elderly patients are likely to have diminished renal function. Ensure monitoring of renal
function. Giving Risperidone and Palperidone LAIs in very small doses (<2mg risperidone oral equivalent) can be
tricky as the vials and syringes are not designed to be used in that way. If giving half or quarter of a syringe,
mistakes in dosing are possible if the suspension is not uniform. Not using the whole syringe is effectively off
licence but clinicians may feel it is indicated. Jacoby (2008, pg. 624) states; “The advent of risperidone injections
has had a disappointingly small impact on the treatment of this patient group, largely because of the high
milligram daily equivalent of the lowest available dose”
There have been oral switching studies from oral FGAs to oral olanzapine and risperidone with positive results for
symptoms and motor side effects (No control group kept on the original medication). Olanzapine did better than
risperidone regarding quality of life. Approx. 12% olanzapine and 27% risperidone failed the cross over due to
treatment failure. (Ritchie 2003, 2006).
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Aripiprazole LAI
There have been no control trials of aripiprazole LAI in the elderly population but some case studies and
retrospective small cohort reviews. Rado (2010) reviewed its oral use in late life schizophrenia. With regards to
oral use, Rado states; “Because of its moderate affinity for the α2 adrenergic receptor, aripiprazole may produce
comparatively less orthostasis, leading to greater tolerability. We note, however, that elderly patients often suffer
from comorbid cardiovascular and cerebrovascular disorders; usually are taking medications (e.g.,
antihypertensives) to manage these conditions; and thus may be at greater risk for complications associated with
the anti-α adrenergic effects of agents such as aripiprazole. Compared with other SGAs, aripiprazole is associated
with a relatively lower risk of metabolic complications such as weight gain, hyperlipidaemia, and diabetes
mellitus” he goes on to intimate that aripiprazole is advantageous in the elderly due to a lack of sedative action
and good QTc profile.
The SPC for aripiprazole LAI states;
“The safety and efficacy of ABILIFY MAINTENA in the treatment of schizophrenia in patients 65 years of age or
older has not been established.”
“After oral administration of aripiprazole, there are no differences in the pharmacokinetics of aripiprazole
between healthy elderly and younger adult subjects. Similarly, there was no detectable effect of age in a
population pharmacokinetic analysis of ABILIFY MAINTENA in schizophrenia patients.” Denning(2014, pg. 611)
suggests some writers recommend a modest dosage range of 10-15mg. Take care if low albumin as aripiprazole
may become un-protein bound and circulate at effectively higher doses.
If necessary Aripiprazole LAI can be more easily given in smaller doses than Risperidone or paliperidone LAI,
because of the way it is drawn up. However there is not a linear relationship between dose and plasma levels.
Mallikaarjun (2013) demonstrated that the relationship between dose and plasma levels was not linear, with
300mg and 400mg giving similar plasma levels, but 200mg resulting in proportionately much lower plasma levels.
The 300mg-400mg dosing range was equivalent to an oral dosing range of 10-30-mg with greater variation in
plasma levels for the LAI compared to oral medication. In LAI form like the FGAs EPSE side effect burden seems to
increase. SEE BOX N for pharmacodynamics of aripiprazole.
Olanzapine LAI
SPC for Olanzapine LAI states;
“ZYPADHERA has not been systematically studied in elderly patients (> 65 years). ZYPADHERA is not
recommended for treatment in the elderly population unless a well-tolerated and effective dose regimen using
oral olanzapine has been established. A lower starting dose (150 mg/4 weeks) is not routinely indicated, but
should be considered for those 65 and over when clinical factors warrant. ZYPADHERA is not recommended to be
started in patients >75 years (see section 4.4).” 150mg every 4 weeks probably equates to about 5mg orally a day.
Like Aripiprazole LAI. Olanzapine LAI can be more easily given in smaller doses than Risperidone or paliperidone
LAI, because of the way it is drawn up.
There have been oral switching studies from oral FGAs to oral olanzapine and risperidone with positive results for
symptoms and motor side effects (No control group kept on the original medication). Olanzapine did better than
risperidone regarding quality of life. Approx. 12% olanzapine and 27% risperidone failed the cross over due to
treatment failure. (Ritchie 2003, 2006).
Elderly patients with dementia. Regarding what is stated in SPC’s; Risperdal consta has not been
studied in elderly patients with dementia, hence it is not recommended for use in this group of patients.
The Xeplion SPC says use with caution. The Trevicta SPC says do not use. Specifically regarding
behavioural management of dementia oral risperidone is licenced for persistent aggression in
Alzheimer’s dementia at small doses for up to 6 weeks. No LAI has a licence for this indication. Where
one may be considered in unusual circumstances is beyond the remit of this document. There is trust
guidance elsewhere for the behavioural management of dementia (see PG 14) See also Maudsley pg.
510-511. Consider covert use of oral medication.
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Appendix 2. Differences between Risperidone LAI and Paliperidone LAI.
The Department of Health in Australia (2010, see references) reviewed the use of paliperidone and based on their
Medicare data questioned the equivalent doses of Paliperidone LAI and Risperidone LAI. It is currently generally
accepted that a ratio of 1:1 is appropriate. It is possible that higher doses of paliperidone are needed compared
to risperidone as paliperidone is a less potent D2 receptor agonist and does not cross the blood brain barrier as
well. However Risperidone is quickly converted by the liver into paliperidone and for individuals on risperidone
their blood levels of paliperidone are 5-10 times higher than risperidone. Therefore molecular differences are
likely to have minor effect. Also as paliperidone LAI is dosed monthly rather than 4 weekly a slightly lower
equivalent dose is being administered. The Australians still concluded that it was cost effective. Recent research
from SLAM suggests that clients stay on paliperidone LAI significantly longer than they do Risperidone LAI (see
below). The Scottish medicines consortium concluded Paliperidone LAI was cost effective compared to Risperdal
LAI.
Table 2. The advantages/disadvantages of Paliperidone LAI are as follows.
Paliperidone LAI Property (Xeplion)
Clinical advantage
Monthly injections
Better patient compliance.
May be given 7 days before or after usual date of Helps avoid missed doses in chaotic patients.
administration
Much faster onset of action than Risperidone so Can be used in currently non-orally compliant patients.
does not require oral supplementation on
Risperidone LAI cannot be used in this scenario due to its
initiation of therapy.
very delayed onset of action, meaning oral cover is
needed for at least 3 weeks
Available as a pre-filled syringe with a smaller
Less wastage than Risperidone LAI which requires cold
administration volume that does not require
chain transport and storage. Lower volume of
refrigeration
Paliperidone LAI more patient friendly.
Wider licensed dosing range
More Flexible.
Less drug interactions as not as extensively
metabolised in the liver as risperidone is.
The paliperidone LAI SPC that suggests 50mg
Risperdal LAI every 2 weeks = 100mg This may
not be correct. Reasons given above. Australian
data suggested a Risp: Palip dosing ratio of 1:1.3.
First 2 doses should be given into deltoid to get a
rapid response.
Long half-life and dose kinetics means
paliperidone stays in the plasma long time.
Good choice of LAI for those with liver failure, or those
with polypharmacy, at risk of drug interactions.
Potential Advantages/Disadvantages
Awareness of this possible discrepancy is especially
important if changing individuals from risperidone to
paliperidone, as they may relapse on SPC equivalent
doses. Disadvantage of unexpected financial cost of
having to give higher paliperidone dose.
In the non-enthusiastic patient this could be an advantage
or disadvantage. FGAs should be given in the gluteal
which puts patients off. However in a restraint situation it
is much safer to administer in the gluteal. (section 8
below) but Risperidone LAI cannot be used for non- orally
compliant patients anyway
Advantage in steady state as minimal plasma level
fluctuations. Potential disadvantage of unknown side
effects if given without prior knowledge of oral tolerance
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(off licence use). Risperidone LAI
The information below comes from David Taylor (2013), Chief pharmacist at the South London and Maudsley NHS
Foundation Trust, and editor of “The Maudsley Prescribing Guidelines in Psychiatry.” The graph shows how well
paliperidone (PP) LAI is tolerated for the first year of its use, based on as yet unpublished data from a prospective
trial done in the Maudsley trust. The data for Risperdal Consta comes from a similar trial done by Taylor (2009).
TREVICTA
Since 2018 Trevicta a 3 monthly preparation of paliperidone has also become available. The obvious advantage
of this preparation is less injections. The disadvantage is if there are side effects they may be long lasting and
careful consideration needs to be given to a clients renal function before moving between Xeplion and Trevicta.
The conversion ratio for dosing is 3.5 rather than 3. (see equivalent doses in section 3 under licencing)
From the SPC;
“Due to its extremely low water solubility (Trevicta), the 3-monthly formulation of paliperidone palmitate dissolves
slowly after intramuscular injection before being hydrolysed to paliperidone and absorbed into the systemic
circulation. The release of the active substance starts as early as day 1 and lasts for as long as 18 months..
TREVICTA, when administered at doses that are 3.5-fold higher than the corresponding dose of 1-monthly
paliperidone palmitate injection (see section 4.2), results in paliperidone exposures similar to those obtained with
corresponding monthly doses of 1-monthly paliperidone palmitate injection”
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