This document discusses long-acting injectable (LAI) antipsychotics for the management of schizophrenia. It provides an overview of the biology and outcomes of schizophrenia, including high relapse rates when treatment is discontinued. Relapse is associated with increased dopamine function and may be linked to disease progression. LAI antipsychotics can help improve adherence and reduce relapse rates compared to oral antipsychotics. The document reviews guidelines recommending LAI use and discusses patients' and clinicians' positive attitudes towards LAIs. It also covers the receptor profile and attributes of paliperidone palmitate, an atypical LAI antipsychotic.

2. LAT for the Management of
Schizophrenia
Prof. Hani Hamed Dessoki, M.D.Psychiatry
Prof. Psychiatry
Acting Dean, Faculty of Applied Mental Health sciences
Beni Suef University
Supervisor of Psychiatry Department
El-Fayoum University
APA member
2017

3. Disclosure
Prof. Hani H. Dessoki, MD Psychiatry, has disclosed the following relevant
financial relationships:
• Served as an advisor or consultant for: Lundbeck, Inc.; Hikma
Pharmaceutical PLC; Apex Multi-Apex Pharma.
• Served as a speaker for: AstraZeneca Pharmaceuticals LP; Eli Lilly and
Company; Janssen Pharmaceuticals Inc; Lundbeck, Inc.; Otsuka
Pharmaceutical Co., Ltd.; Pfizer Inc.; Hikma Pharmaceutical PLC; Apex Multi-
Apex Pharma, Mash Primeire For Pharmaceutical Industry.
• Some promotional data provided by Janssen.

4. Objectives
• Introduction
• Biology of schizophrenia
• Outcome & Relapse rate
• Biology of relapse
• When and why LAT
• Take Home Message
• Recent data

6. Schizophrenia Spectrum Disorders
• The prevalences of schizophrenia and schizophrenia-
related personality disorders in the general
population are 1% and 5%, respectively; the
prevalence of both together is 6%.
• Approximately 20% of family members of an individual
with schizophrenia have spectrum manifestations.
• Moreover, approximately 20% of persons with
spectrum manifestations have symptoms that are
severe enough to impair work function and may
benefit from antipsychotic treatment

8. Response
Remission
Relapse
Emergent
refractoriness
RECOVERY
ACUTE PSYCHOTIC
EPISODE
Partial
response
Autonomy
Independent living
Quality of life
Social and
occupational
functioning
Shaping a future for schizophrenia patients

10. Dopamine hypothesis of schizophrenia
Nigrostriatal
pathway
(part of extrapyramidal
motor system)
Tuberoinfundibular
pathway
(inhibits prolactin release)
Mesocortical
pathway
Hypoactivity:
negative symptoms,
cognitive impairment
Hyperactivity:
positive symptoms
Mesolimbic
pathway
Adapted from: Inoue & Nakata. Jpn J Pharmacol 2001;86:376–38010

11. Differential effects of receptor blockade in
key dopamine pathways (1)
• Excess dopamine is associated with positive symptoms
• D2 receptor blockade in this pathway can help reduce
positive symptoms
Mesolimbic
pathway
• Deficits in dopamine are associated with negative and
cognitive symptoms
• The mesocortical pathway is rich in 5-HT2A receptors
• Serotonin receptor antagonists increase dopamine levels
and alleviate negative and cognitive symptoms
Mesocortical
pathway
D, dopamine; 5-HT, serotonergic
Adapted from: Stahl. Stahl’s Essential Psychopharmacology. 3rd edition. 2008
11

12. • Forms part of the extrapyramidal system and mediates
motor control
• Dopamine receptor antagonism causes movement disorders such
as EPS
• 5-HT2A antagonists disinhibit dopamine release, and may
alleviate EPS
Nigrostriatal
pathway
• Dopamine activity inhibits prolactin release, whereas serotonin
stimulates its release
• Blockade of D2 receptors increases prolactin release and may cause
sexual side effects
• Balancing dopamine and 5-HT2A antagonism is critical
Tubero-
infundibular
pathway
EPS, extrapyramidal symptoms;
TD, tardive dyskinesia; 5-HT, serotonergic; D, dopamine
Differential effects of receptor blockade in
key dopamine pathways (2)
Adapted from: Stahl. Stahl’s Essential Psychopharmacology. 3rd edition. 2008
12

13. • In order to fully understand
the properties of
antipsychotics, it is
imperative to examine the
serotonin (5HT) pathways
throughout the brain and
how they modulate DA
and glutamate circuits.
Key Serotonin Pathways

14. • 5HT1A is dopamine accelerator. However, 5HT2A is dopamine brake
(opposite effect is on glutamate).

16. Glutamate acts as accelerator on dopamine in
mesocortical area, and act as a brake in mesolimbic
area.

17. Basic Conclusion
• Glutamate acts as accelerator on dop. in mesocortical area.
• Glutamate acts as brake on dop. in mesolimbic area.
• 5HT 1A acts as accelerator on dop.
• 5HT2A acts as brake on dop.
• 5HT 1A acts as brake on glutamate.
• 5HT2A acts as accelerator on glutamate.
So, atypical antipsychotics (mainly serotonergic, can decrease
dopamine in mesolimbic area by 2 mechanisms 1st: it’s
brake effect on dopamine through 5HT2A, and the 2nd is
it’s accelerator effect on glutamate which is brake on
dopamine).

18. Future of Biology
• The availability of the very new resource of
the sequenced human genome is challenging
our field to take advantage of this critical
genetic information.
• Tracing the genetic basis of the cerebral
mechanisms that, might, express a particular
genetic defect in psychosis or in a disease like
schizophrenia will require specific information
about, the human schizophrenic brain.

19. Outcomes in schizophrenia
• Long-term clinical outcomes are variable. Approximately
10–15% of patients will not experience further episodes
• The majority of patients display exacerbations and
experience clinical deterioration
• From the outset, 10–15% of patients remain chronically,
severely psychotic
Long-term clinical
outcomes are
variable1
•Associated with clinical deterioration2
•High level of distress and burden for carers3
Early in the disease
course, patients
respond well to
treatment but
frequently relapse2
1. APA Practice Guidelines, 2004. http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=
Schizophrenia2ePG_05-15-06; 2. Robinson et al. Arch Gen Psychiatry 1999;56:241–247;
3. Awad & Voruganti. Pharmacoeconomics 2008;26:149–16219

20. Recovery in schizophrenia
This review concluded that 42% of patients had a good
outcome
13.5% of patients met recovery criteria
Recovery may be treatment-related or spontaneous
20
Jääskeläinen et al. Schizophr Bull 2012. Nov 20 [Epub ahead of print]
• Jääskeläinen et al meta-analysis of 50 studies
• Primary aims were to:
• Identify the proportion of individuals with schizophrenia and related psychoses
who met recovery criteria
• Examine which factors were associated with recovery

22. Risk and protective factors for relapse
among Individuals with Schizophrenia
• People with schizophrenia and their caregivers perceived non
adherence to antipsychotic medication as a leading risk factor of
relapse; other risks included poor family support, stressful life
events and substance use.
• Family support, adherence to antipsychotic medication,
employment and religion were viewed as protective factors.
• Participants suggested strengthening mental health psycho-
education sessions and community home visits conducted by
mental health nurses to help reduce relapse.
BMC Psychaitry,2014

23. The Nature of Relapse in Schizophrenia
• Relapse rates are very high when treatment is
discontinued, even after a single psychotic episode; a
longer treatment period prior to discontinuation does
not reduce the risk of relapse.
• Many patients relapse soon after treatment reduction
and discontinuation; transition from remission to
relapse may be abrupt and with few or no early
warning signs.
• The response time is variable and notably, treatment
failure appears to emerge in about 1 in 6 patients.
BMC Psychiatry2013, 13:50

24. Is relapse associated with disease
progression?
• Active psychosis may affect the brain in a
more fundamental way. It has been suggested
that psychosis may be neurotoxic and that
acute psychotic exacerbations represent active
periods of a morbid process that leads to
disease progression and to impairment of
treatment response.

25. Is relapse associated with disease
progression?
• Treatment response has been observed to be
better in first-episode schizophrenia than in
chronic multi-episode schizophrenia .
• A study utilizing the neuroleptic threshold
principle found that first-episode patients
required lower doses of haloperidol to
achieve optimal clinical response than multi-
episode patients.

26. Neurobiology of Relapse in
Schizophrenia
• The dopamine hypothesis of schizophrenia has
been central to our understanding of
neurobiological mechanisms underpinning the
illness, and dopamine D2 receptor blockade
remains a necessary and sufficient component for
antipsychotic action.
• Therefore relapse, characterized by acute
psychotic exacerbation, would be associated with
striatal dopamine hyperfunction, likely as
elevation of presynaptic dopamine synthesis.

27. Neurobiology of Relapse in
Schizophrenia
• Cortical and limbic striatal (nucleus accumbens)
dopamine release is regulated by a glutamate-
GABA-glutamate loop located on pyramidal cells
of the frontal cortex.
• Cortical hypoglutamatergia in turn compromises
dopamine release in the ventral tegmentum
leading to meso-limbic hyperdopaminergic and
meso-cortical hypodopaminergia that we
observe as positive or negative symptoms,
respectively.

28. Neurobiology of Relapse in
Schizophrenia
• Mesolimbic dopaminergic supersensitivity
after chronic antipsychotic treatment could
explain the emergence of antipsychotic
treatment failure.
• The kindling phenomenon has also been
linked to increased excitatory glutamatergic
activity combined with a relative loss of
inhibitory GABA’ergic tone

29. Relapse Prevention
• 5y, Relapse rate 82% (16%  54%  63%  75%  82%).
• after discharge, 8% stop taking antipsychotics
• relapse rate of 3.5% of patients/month with good adherence.
• Atypical vs Conventional (23% Vs 15%).
• Strongest Predictors of Relapse is Adherence/ length of treatment
Decreasing relapse:
• Wishful thinking
• Integrated strategy approach
• Oral Vs Injectables

30. Clinical impact of treatment-related
adverse events
• The patient’s subjective experience of treatment-related adverse events contributes to their
assessment of a drug
• In clinical practice, patients should be informed of common side effects prior to treatment
• Individual tolerability is unpredictable; close monitoring is required
• Different side effects affect patients differently; sometimes related to gender, age
and physical condition
Adapted from Hamer & Haddad. Br J Psychiatry 2007;191:s64–s70; Marder et al. Schizophr Bull 2002;28:5‒16
Poor
adherence
Relapse
Chronic
symptoms
Reduced
quality
of life
Stigma
Physical
morbidity
and mortality
30
SGA
FGA
FGA, first-generation antipsychotic; SGA, second-generation antipsychotic
Adverse
events

31. Under-treatment with FGAs: EPS are most disturbing
Under-treatment with SGAs: sexual side effects,
weight gain and sedation can be problematic
High inter-individual variation
Taylor et al. The Maudsley Prescribing Guidelines in Psychiatry.
11th edition; Chichester: Wiley-Blackwell; 2012
FGA, first-generation antipsychotic; EPS, extrapyramidal symptoms;
SGA, second-generation antipsychotic
31
Impact of side effects on subjective
well-being

32. Guidelines recommend offering
early intervention services
• Urgently refer all people with first-episode psychosis to a local community-based
secondary mental health service
Offer early intervention services to all patients with
a first psychotic episode1
• Pharmacological, psychological, social, occupational and educational services
Early intervention services should aim to provide a full
range of:1
• Encourage patients to collaborate on the selection and adjustment of treatment
Develop a therapeutic alliance with the patient and their
family during acute phases of illness2
1. Barnes. J Psychopharmacol 2011;25:567–620;
2. APA Practice Guidelines, 2004.
http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=Schizophrenia2ePG_05-15-0632

33. Guidelines for the use and management of LAI
AP in serious mental illness 1
French Society for Biological Psychiatry
• Key points
– LAI antipsychotics should be considered and systematically proposed
to any patients for whom maintenance antipsychotic treatment is
indicated
– It is recommended to deliver to each patient specific information
concerning the advantages and inconveniences of the LAI
formulation, in the framework of shared decision-making.
1. Llorca et al (2013)

34. History of LAIs
• Long-acting injectable antipsychotics (LAIs) are a
pharmacotherapeutic option to help clinicians
individualize schizophrenia treatment.
• LAIs have been available since the 1960s, starting
with fluphenazine and later haloperidol; however,
second-generation antipsychotics were not
available in the United States until 2007.

35. Clinical pearls
• Before prescribing an LAI, check that your
patient has no known contraindications to the
active drug or delivery method.
• Peak-related adverse effects typically are not
contraindications, although they may prompt
you to start at a lower dose.

36. Benefits of LAT Antipsychotic 1
• Controlled administration :
– Early identification of non adherence
– Improved adherence
– Clear attribution of cause of relapse or non response
• Regular interactions between patient and
healthcare provider
• Improved interaction with family
1. Kane JM and Garcia-Ribera (2009)

37. Objectives for LAI development:
◎Early onset of efficacy
◎Constant drug release over weeks/months
◎Good tolerability
◎ At injection site, weight gain, EPMS, low drug-drug-interaction…
◎Convenience/ handling
◎ Prefilled syringe
◎ Storage at room temperature
◎ gluteal and deltoid injection available
37

38. Opinions of patients with schizophrenia
regarding LAI
• Survey in which 206 French schizophrenia patients were
interviewed 1
– Ninety-five percent had been treated with more than one form of
dosage
• Injections were being preferred by 47% of patients
• Oral tablets were being preferred by 35% of patients
• Drops were being preferred by 7% of patients
• 51% considered injectable therapy to be more effective than other
medication
• 70% felt better supported in their illness by the regular contact with
the caregivers
1. Caroli et al (2012)

39. Attitudes of Psychiatrists and Nurses
• Recently, a survey of 891 European
psychiatrists and nurses revealed that 96%
preferred LAI medications to oral treatment
for patients with chronic schizophrenia,
whereas only 40% preferred them for first-
episode patients [Geerts et al. 2013].

40. Cost-effectiveness of LAI AP
treatment
• Finally, increase in medication adherence with the use
of LAI APs may eventually induce a reduction in the
pharmaceutical costs of schizophrenia treatment by a
decrease in hospital stays that compensate their
higher costs, especially SGAs [Niaz and Haddad, 2010].
• Treatment with LAIs may be also more cost-effective
than oral medication, and may reduce the suicide risk
and the greater propensity to violence observed at
least in a subset of persons with psychotic illnesses and
comorbid substance/alcohol use disorders [Ravasio et
al. 2009; Reichart and Kissling, 2013].

41. Paliperidone Palmitate Receptor
Profile

42. Paliperidone palmitate – Key attributes
Paliperidone palmitate1
Formulation Aqueous-based suspension
Treatment initiation
Initiation injections on Day 1 and Day 8; no oral
supplementation required
Maintenance dosing Once-monthly injection
Administration Deltoid and gluteal IM
Dosage range
25, 50, 75, 100 and
150 mg eq.
How supplied
No reconstitution required;
prefilled syringes
Storage No refrigeration required
Needle supplied or
recommended
1 inch (25mm) 23G or 1½inch (38mm) 22G needle
(depending on patient weight and injection site)
Post-injection monitoring No*
1. Proposed Xeplion® EU SmPC; 2. Alphs et al. Curr Drug Saf. 2011; 6:43–45
LAI, long-acting injectable; RLAI, risperidone long-acting injectable;
IM, intramuscular; UTW, ultra thin wall; TW, thin wall
* No cases of PDSS were identified in an analysis of completed trials2

43. • Broad dose range
• 50, 75, 100, 150 mg (~ 25, 37.5, 50, 75 mg Risperidone LAI)
• Small volume of injection
• 0.5, 0.75, 1.0, 1.5 mL
• Deltoid and gluteal administration
• Deltoid quicker steady state (see later)
• Greater patient choice
Paliperidone – dosing &
indication

44. Deltoid administration – higher Cmax and AUCτ, but similar tmax and
AUC∞
1. Xeplion® EU SmPC; 2. Cleton et al. Poster no. PI-75 presented at ASCPT: Orlando, April 2–5, 2008
Paliperidone – Deltoid vs Gluteal profile

45. *Recommended monthly dose
**Some patients may benefit from lower or higher doses based on individual patient tolerability and/or efficacy. Patients who are overweight
or obese may require doses in the upper range
†A switch from gluteal to deltoid (and vice versa) should be considered in the event of injection site pain (if discomfort is not well tolerated).It is
also recommended to alternate between
left and right sides
INITIATION REGIMEN MAINTENANCE REGIMEN
(1 month after 2nd initiation dose)
Day 1 Day 8
+/- 2 days
150 mg eq.
Deltoid
100 mg
eq. Deltoid
1 month later
+/- 7 days
1 month later
+/- 7 days
Dose range**
25–150 mg eq.
Deltoid/gluteal†
Dose range**
25–150 mg eq.
Deltoid/gluteal†
75 mg eq.
(recommended*)
Deltoid/gluteal†
75 mg eq.
(recommended*)
Deltoid/gluteal†
Xeplion® EU SmPC; Gopal et al. Curr Med Res Opin 2010;26:377–387
Paliperidone – Adminsration

46. Risperdal Consta Xeplion®
2 weekly injection Monthly injection
Requires cold storage No cold chain
3 weeks delay Fast Onset
Oral Supplementation No oral Supplementation
3 available doses 4 available doses
19 Steps to Inject Inject and go
Xeplion®: Product summary

47. ROLE OF PSYCHOSOCIAL
INTERVENTIONS
47

48. What are the goals of integrated care?
• Reduce the symptoms experienced by patients1,2
• Reduce periods in hospitals3
• Reduce the risk of relapse4
• Preserve patients’ long-term functioning3
• Improve quality of life5
• Improve neurological and social cognition6
• Help patients to develop larger social networks7
• Help patients to find and retain competitive
employment and live independently8,9
Good management of schizophrenia can:
1. Emsley et al. Int Clin Psychopharmacol 2008;23:325–331; 2. Emsley et al. J Clin Psychopharmacol 2008;28:210–213;
3. Peuskens et al. Curr Med Res Opin 2010;26:501–509; 4. Kane. N Engl J Med 1996;334:34–41; 5. Ascher-Svanum et al. J Clin
Psychiatry 2006;67:1114–1123; 6. Roder et al. Schizophr Bull 2011;37(suppl 2):S71–S79; 7. Tempier et al. Psychiatr Serv
2012;63:216–222; 8. Twamley et al. J Nerv Ment Dis 2005;193:596–601; 9. Burns et al. Lancet 2007;370:1146–1152
48

49. Take Home Messages
• Adherence is an issue in long term treatment of
schizophrenia and is frequently underestimated
• LAT has a demonstrated efficacy for relapse
prevention and long term treatment of
schizophrenia
• LAT is an option to be proposed to all patients
with schizophrenia needing a maintenance
treatment even in the early phase of illness
• Patients’ perspective is neutral or positive on LAT

50. Recent Data
• FDA Approves New Three-Month Long-Acting Antipsychotic Invega Trinza
(Trevicta)
•
The FDA has approved Invega Trinza (paliperidone palmitate), a long-acting atypical
antipsychotic intended to treat schizophrenia, from Janssen Pharmaceuticals Inc.
The approval of the injectable antipsychotic, which remains active in the body for
three months, was based on results from a two-year maintenance trial with 506
patients diagnosed with schizophrenia. Theanalysis, published March 29 in JAMA
Psychiatry, showed that patients who were administered Invega Trinza were
statistically less likely to relapse than those who were administered placebo. The
most common adverse effects of the medication included injection-site reactions,
weight gain, upper respiratory tract infections, and extrapyramidal symptoms.
Invega Trinza was approved under the FDA's priority review process, a fast track for
drugs thought to represent a significant advance in medical care. It is being marketed
by Janssen.
For more information about psychotropic medications in the pipeline, see
thePsychiatric News article "Candidates, Innovation Missing From Psychotropic Drug
Pipeline."

52. Scientists find chemical pathway
responsible for schizophrenia symptoms
• Recent studies have suggested that kynurenic acid (KYNA) plays a
key role in the pathophysiology of schizophrenia. People with
schizophrenia have been shown to possess higher levels of KYNA
than healthy individuals.
• KYNA helps to metabolize tryptophan - an essential amino acid
that, in turn, helps the body to produce the "happiness"
neurotransmitter serotonin, and the vitamin niacin.
• Additionally, KYNA decreases glutamate - a nonessential amino acid
widely recognized as the most important neurotransmitter for
healthy brain functioning.
Biological Psychiatry, 2016