A recent update regarding various long acting injectables used in schizophrenia, comparison with oral antipsychotics and current scenario in India.

1. Long Acting Injectables (LAIs) in
Schizophrenia- An Overview
Dr. Sumesh Balachandran
Assistant Professor
Department of Psychiatry
GMC Kannur, Kerala

2. Contents
• Introduction
• Different types of AP formulations
• SGA LAIs
• Bio-availability and Dosing
• Attitude of Clinicians and patients towards LAIs
• Importance of ensuring treatment continuity and consequences of non-adherence
• Guidelines
• AP discontinuation after FES
• Comparative studies
• Pros and cons of LAIs
• Points to wonder and ponder
• Indian perspective
• Conclusion
• Directions for future research

3. Introduction
• Schizophrenia is “a mental disorder that is characterized by disturbances in
thought (such as delusions), perception (such as hallucinations), and behavior
(such as disorganized speech or catatonic behavior), loss of emotional
responsiveness and extreme apathy, and by noticeable deterioration in the level
of functioning in everyday life”.
• Affects language, planning, emotion, perceptions, and movement.
• Benedict Morel (1809–1873), a French psychiatrist, had used the term démence
précoce to describe deteriorated patients whose illnesses began in adolescence.

4. • In 1887, German Physician, Dr. Emile Kraeplin coined the term “Dementia
Praecox” for individuals who had symptoms that are now associated with
schizophrenia.
• Functional deterioration tends to occur in the first 5 years after onset of
schizophrenia.
• Later the illness typically progresses into a stable phase.
Positive symptoms are decreased
Negative, and cognitive symptoms become predominant.
• Schizophrenia is a mostly chronic mental disorder.

5. • Symptomatic relapse is frequently observed.
• It is often associated with social and/or occupational decline that
can be difficult to reverse.
• Most patients with the illness need long-term pharmacological
treatment.
• Antipsychotic drugs represent the mainstay of clinical care.
5

6. Types of AP formulations
• Antipsychotic drugs Oral
Oral Depot
Long Acting Injectables
• Conventional antipsychotics (APs) such as chlorpromazine, fluphenazine
and haloperidol were replaced by clozapine.
• The second generation APs increased tolerability, reduced relapse risk, and
improved quality of life.
6

7. • The introduction of the oral second-generation APs (SGAs) brought claims of
better tolerance and less severe side effects (metabolic syndrome may curb
their use).
• They also have potential to prevent or reverse accelerated frontotemporal
cortical grey matter decline.
• They provide a greater degree of neuroprotection than first generation APs
(FGAs).
• The introduction of SGAs led to a decline in the use of LAI FGAs.
(Patel and David, 2005)
• Atypical characteristics did not bring better adherence rates with oral SGAs.
7

8. Oral Depot Medication
• Penfluridol is a long-acting oral antipsychotic agent for the treatment of
schizophrenia.
• It has a unique property of lipophilicity.
• Distributes extensively in fatty tissues following oral administration.
• This depot effect produces a very slow release of drug from the tissues and
results in a very long duration of activity.
• Doses of 20–100 mg/week are efficacious.
• The efficacy and adverse effects profile of penfluridol are similar to other typical
APs; both oral and depot. 8

9. Penfluridol (contd.)
• Penfluridol is shown to be a treatment option for people with poor
response to oral medication daily and do not adapt well to depot drugs.
• A lower dropout rate in medium term when compared to depot
medications.
• It is a treatment option for chronic schizophrenia patients with residual
psychotic symptoms who nevertheless need continuous use of
antipsychotic medication.
• It is a low-cost intervention.
9

10. Long Acting Injections Antipsychotics
(LAI APs)

11. 11

12. Second Generation LAI

13. Risperidone long-acting injectables
• RLAI is indicated in the maintenance treatment of schizophrenia in
patients on oral APs.
• RLAI is not recommended for patients below 18 years of age.
• Dosage Before the first injection of RLAI, the patient is recommended
to be on oral risperidone no shorter than 2 weeks.
• RLAI doses are available as: 25, 37.5, and 50 mg.
13

14. • RLAI should be used in the lowest effective dose, usually given every 2
weeks.
• The administration of RLAI less frequently than every four weeks is not
recommended.
• In the event of discontinuation, it needs to be taken into account that the
risperidone level will maintain for at least 3 weeks after the last injection.
• RLAI dose can be increased every 4 weeks.
• The maximum RLAI dosage is 50 mg every 2 weeks. In the elderly, the usual
RLAI dosage is 25 mg every 2 weeks.

16. • Side-effects are insomnia, anxiety, headache, upper respiratory tract
infections, depression, akathisia, and an increase in prolactin level.
• The use in patients with dementia or with cerebrovascular disorders
requires caution. There is a higher risk of morbidity and mortality in
these patients.
• The drug interactions are with L-dopa and DA-agonists, phenothiazines,
tricyclic antidepressants, β-blockers, lithium, valproate, and donepezil.
16

17. Olanzapine long-acting injectables
• Indicated for the maintenance treatment of adult schizophrenic patients
who have been stabilized on oral olanzapine.
• Dosage OLAI is available in three doses: 210, 300 and 405 mg of olanzapine
pamoate monohydrate powder and solvent for prolonged-release
suspension for injections.
• The half-life of OLAI is 30 days.
• When the patient had already been stabilized on oral olanzapine, the OLAI
should be given at the lowest possible dosage, usually at the intervals of 2-
4 weeks.
17

18. • The drug should be administered deeply into the gluteal muscle.
• The administration of the drug should take place under conditions which
allow for observation of patient to look out for postinjection syndrome.
• For maintenance treatment in schizophrenia usually, the lowest possible
dose of OLAI is administered every 4 weeks.
• The oral dose can be given simultaneously, but the total equivalent dose
should not exceed 20 mg.
• The dose should be reduced in the presence of factors which can slow
down the olanzapine metabolism, such as female gender, older age, and
nonsmoking patient. 18

19. • The adverse effects for olanzapine use include the risk of body weight gain, and
metabolic syndrome, abnormal lipids levels as well as hyperglycemia
• Side-effects at the injection site were seen in about 8% of patients.
• The most common injection site side-effect was pain in about 5% of patients.
• Postinjection syndrome is a rare complication of OLAI treatment which has been
noted less frequently (1/1000 OLAI injections).
• Due to its symptoms: sedation and/or delirium, agitation, anxiety, and cognitive
dysfunctions, after every OLAI injection, the patient has to be under the close
supervision of medical personnel for three hours.
• As it produces stable serum levels, the OLAI may be better tolerated in terms of
somnolence, fatigue, and orthostatic hypotension than oral olanzapine.
• Its metabolism can be induced by tobacco smoking and carbamazepine taking
which may result in lowering olanzapine levels. Fluvoxamine and ciprofloxacin
cause a significant inhibition of olanzapine metabolism. 19

20. Aripiprazole long-acting injectables
• Indicated for maintenance treatment of patients with schizophrenia who have
been stabilized by oral antipsychotic treatment.
• ALAI is not indicated for elderly and dementia patients.
•
• It is not indicated for patients less than 18 years.
• Dosage Patients who have not been treated with aripiprazole before the initiation
of ALAI should at first be treated with aripiprazole administered orally.
• Those who have already been treated with oral aripiprazole should receive 400
mg of ALAI with the simultaneous continuation of oral aripiprazole for 14 days to
assure stable serum aripiprazole levels.
20

21. • ALAI injections should be given every 4 weeks.
• In case of intolerance, the dose can be decreased to 300 mg, every 4 weeks.
• The half-life (T1/2) of ALAI given in a dose of 400 mg is 47 days, and for 300 mg,
30 days.
• Aripiprazole lauroxil has a 1-day treatment initiation option where the patient
can receive a single 662-mg aripiprazole lauroxil injection plus 30-mg oral
aripiprazole followed by either 441-mg or 882-mg aripiprazole lauroxil injection.
• The most common ALAI side-effects are pain at injection site, insomnia, akathisia,
and body mass change.
• Aripiprazole is metabolized with the use of isoenzymes 3A4 and 2D6 of the
cytochrome P450. Drug interactions - carbamazepine and ketoconazole.

22. Paliperidone long-acting injectables
• Indicated in schizophrenia patients after at least one relapse or exacerbation of symptoms
in the patient’s history caused by the persistent lack of adherence to treatment, who
respond to treatment with risperidone and paliperidone.
• PLAI should be used in patients who have been stabilized under risperidone or
paliperidone treatment.
• In selected patients who have previously shown a favorable response to oral paliperidone
or risperidone, PLAI can be used without the previous stabilization of patients with oral
antipsychotic treatment.
• PLAI should not be used for patients with acute psychoses and/or those who require
immediate sedation.
• The use of PLAI in the population of elderly patients has not been studied.
22

23. • PLAI is available in the doses of (suspension for injection with
prolonged release) 25, 50, 75, 100, and 150 mg.
• The initiation of treatment is recommended with the 150 mg dose
and after a week (8 days after the first injection) a dose of 100 mg
should be given.
• Both injections should be given into the deltoid muscle to reach the
therapeutic serum level of paliperidone as quickly as possible.
• The recommended maintenance dose is 75 mg monthly; in the range
from 25 to 150 mg, depending on individual tolerability and efficacy.
Obese or overweight patients may require higher doses.
23

24. • Side-effects are insomnia, headache, body weight increase, injection site
reactions, agitation, somnolence, akathisia (dose-dependent), nausea,
constipation, dizziness, tremor, vomiting, orthostatic hypotension,
diarrhea, and tachycardia.
• Caution- patients who suffer from cardiovascular diseases or have
prolonged QTc or have disturbances of cerebral circulation.
• In the case that the symptoms of tardive dyskinesia are present, the
discontinuation of the antipsychotic drug should be considered.
• The drug should not be given in patients with moderate to severe renal
conditions or with serious liver failure.
• Drug interactions of PLAI are with drugs that may prolong the QTc interval,
for instance with antiarrhythmic drugs such as disopyramide, amiodarone,
or sotalol, as well as with some antihistaminic drugs and carbamazepine.

25. Bioavailability and dosing of LAI APs
• After getting converted to active and inactive metabolites, only a relatively small portion of oral APs
reaches the brain.
• LAIs bypass the initial deactivating process by avoiding first-pass metabolism in the liver.
• In this way, a higher proportion of the drug is available centrally which arguably can allow the use of
the lowest effective dose.
• As a rule, calculation of total doses for oral versus LAI APs over time will usually show lower doses for
the LAIs.
• Appropriate prescribing and dosing of LAIs is complicated by their long half-lives, delayed release and
risk of postinjection delirium/sedation syndrome.
(Novakovic et al. 2013)
• Even where fixed-dose studies have established ‘dose-response’ curves, lack of clear dose–response
data lead clinicians to approximate dosing in their clinical practice.
25

26. Attitude of Clinicians and Patients towards LAI
APs
• Dearth of studies.
• A negative attitude amongst clinicians regarding LAI APs is common.
• Its more when considering recent onset patients.
• 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]
• The overestimated compliance by psychiatrists also limits their use.
26

27. • Patients have a negative impression of LAIs and perceive them as more
coercive.
• Patients are thought to be more negative towards LAIs than psychiatrists
and relatives.
• Patients are often not fully informed about LAIs by their psychiatrist.
[Patel et al. 2010]
• Treatment decisions are usually made without patient or caregiver input,
with LAIs not being discussed in about 50% of patients taking oral AP
[Potkin et al. 2013]
• However, when offered, more LAI-naïve patients express neutral (47%) or
favourable (16%), rather than unfavourable (37%) responses.
27

29. • Moreover, patients who have tried LAIs prefer this treatment over oral APs
referring that they ‘feel better’, have a more ‘normal life’ and find injections
‘easier to remember’.
• Regarding convenience, both patients and staff show a positive attitude and
satisfaction towards LAIs.
(Wadel and Taylor 2009)
• In subjects with a first episode of psychosis (FEP), psychiatrists frequently
presume that patients will not accept LAI APs.
• Few patients are offered this treatment choice. [Kirschner et al. 2013]
• Although some FEP patients perceive LAI as more coercive and stigmatizing.
• Few have a favourable perception, just like their relatives and primary
caregivers. 29

31. • Two studies found two clusters of factors preferentially considered by
psychiatrists for the prescription of a depot form.
[Heres et al. 2008, Samalin et al. 2013]
• Cluster I corresponded to patients with a history of relapse and poor
compliance with oral forms.
• Patients in (cluster II), which corresponded to patients with a high
level of insight and a high level of therapeutic alliance.
31

32. • Preferential use of LAI APs for patients with behavioural disorders to curb
impulsiveness and aggressiveness or dangerousness.
[Llorca et al. 2013].
• Preference for LAIs is mainly dependent on both the psychiatrists’ and the
patients’ experience with such compounds.
• Educating staff, patients and families can help address prejudice and stigma
towards LAI Aps. [Waddell and Taylor, 2009].
• Increase familiarity and ultimately increase preference for this type of
medication.
[Waddell and Taylor, 2009].
32

33. The ALTO study 2020

34. 34

35. PRELAPSE TRIAL 2019
• John M Kane et al. 2019
• Aim- To document acceptability of treatment with LAI AP
medication to early phase schizophrenia patients
• Results- 91% of the patients accepted at least one LAI AP during
their first three months of their participation

38. • These attitudes determine the prevalence of use of LAIs.
• There is a lack of robust data on the frequency of use of LAI Aps.
• LAI use varies greatly between different regions of the world and over the years.
• The proportion of patients prescribed LAI ranges from 10 to 50%
[De Risio and Lang, 2014].
• Higher prevalence in use (30–50%) is seen in Austria, UK, East Asia, Turkey and
Portugal [De Risio and Lang, 2014]
• Lower numbers have been reported in the USA (13–28%), New Zealand (15%)
and Italy (10%) [De Risio and Lang, 2014].
• Their use is still limited to the maintenance treatment of chronic, multi-episode
schizophrenia. 38

39. The importance of ensuring treatment continuity
in schizophrenia and Consequences of Inadequate
Adherence
•

40. • The relapsing, lifelong course of schizophrenia, along with the potentially progressive nature of
the disease.
• The presence of structural and functional abnormalities in the brain.
• The observed brain abnormalities seem to progress with illness.
• Studies in animal models suggest that chronic exposure to APs may contribute to decreases in
brain tissue volume associated with the disease.
• A significant correlation between greater duration and intensity of AP treatment and reduced
brain tissue volume has also been reported in patients.
40

41. • Prolonged treatment with the SGA RLAI was associated with stable white
matter volume in comparison with a decrease in volume observed in patients
treated with the oral formulation of the same molecule.
[Bartzokis et al. 2012]
• Hence, by modifying adherence, RLAI may differentially impact myelination.
• May account for the better long-term outcomes compared with oral
risperidone.
• The risk–benefit balance of long-term treatment needs to be further assessed.
• Finally, a factor leading to inadequate and/or premature treatment
discontinuation is poor adherence to AP medication.
41

43. The consequences of (in)adequate adherence
to AP treatment
• Medication adherence or compliance is defined as ≥80% of medication taken
over 12 months and/or < 1 week missed medications over 3 months.
(Velligan et al. 2009)
• Poor adherence is a relevant risk factor for relapse in both chronic and
recent-onset patients.
• Most hospital readmissions are because of some degree of nonadherence.
• If is often unclear whether nonadherence is the cause or the consequence of
the relapse.
43

44. Issues Influencing Adherence
• Lack of awareness of illness
• Forgetting to take doses
• Difficulties managing complex regimens (e.g., due to cognitive impairment,
frequency of doses, or number of medications)
• Side effects that are of particular importance to the patient (e.g., weight gain,
akathisia, sexual dysfunction, effects on cognition)
• Financial barriers (e.g., cost, insurance coverage)

45. • Insufficient understanding of medication benefits for symptoms that are
important to the patient
• Ambivalence or suspiciousness of medications or treatment in general
• Lack of a perceived need for treatment (e.g., due to feeling good or not
viewing self as ill)
• Due to personal, religious, or cultural beliefs
• Co-occurring conditions (e.g., depression; alcohol, cannabis, or other
substance use disorder)

46. • High levels of hostility
• Persecutory delusions
• Prior difficulties with adherence
• Prior experiences with treatment (e.g., effectiveness, side effects)
• Limited geographic availability or accessibility of services, financial or
insurance constraints on medications or visits.

47. • Lack of support from significant others for treatment
• Cultural or family beliefs about illness or treatment
• Perceptions of stigma about having an illness and taking medication
• Difficulties in the therapeutic relationship
• Perceived risks and benefits of treatment

48. • Correlates of better adherence
- Better outcomes, as evidenced by an improvement in clinical symptoms and
functioning,
- a reduction in the use of concomitant medication
- the rate of hospitalization and the duration of hospital stay.
• Adherent patients have significantly lower hospital costs than nonadherent
patients
• Better outcomes among adherent patients may be a result of the continuous
availability of medication
• Easier for patients with good functioning levels and better controlled symptoms to
take their medication on a daily basis.
• A key factor for treatment continuity.
• Uninterrupted treatment administration appears to favour good adherence. 48

49. Guidelines and recommendations for the
treatment of schizophrenia with LAI APs
• The first guidelines published in 1998, recommended that LAI APs should be considered for ‘any
patients with schizophrenia for whom long-term treatment is indicated.’
[Kane et al. 1998]
• Several guidelines recommend LAI AP medication only for patients with recurrent relapses
related to partial or full nonadherence, or patients with persistent positive symptoms.
[Lehman et al. 2004; Canadian Psychiatric Association, 2005]
• Texas Medication Algorithm Project recommends that the clinicians consider LAI APs in patients
who are inadequately adherent ‘at any stage’. [Moore et al. 2007]
• Physicians should consider offering LAI APs to patients who would ‘prefer such treatment after
an acute episode and where avoiding covert nonadherence to AP medication is a clinical
priority’ within the treatment plan. [NICE, 2009]
49

50. 50

51. • It should be systematically offered to all patients through shared decision-making.
[Llorca et al. 2013]
• It could reduce the negative image and stigmatization attached to depots.
[Kirschner et al. 2013]
• Several authors propose that LAI APs should not be restricted to patients with
adherence problems and instead should be more widely prescribed.
[Altamura et al. 2012]
• ‘Any patient for whom long-term treatment is indicated should be considered a
candidate for long-acting injections’. {Kane and Garcia-Ribera, 2009]
51

52. Long-acting injectable APs in the early phase
of schizophrenia
• Treatment of FES is particularly important to improve long-term outcomes.
• Most clinical and psychosocial deterioration with cognitive decline and progressive structural
changes in brain volume occur within the first 5 years from the disease onset.
• In this initial phase, pharmacological intervention favourably affect symptomatic control and
functional outcomes.
• The primary goal of treatment during this period is to prevent a subsequent relapse and to restore
socio-occupational functioning to the premorbid level.
[Kim et al. 2013]
• However, poor medication adherence is particularly common in FES.
52

53. • It is among the leading reasons for relapse in FES according to a recent
meta-analysis. [Alvarez-Jiménez et al. 2008]
• This is due to several factors:
- many individuals in the early stages do not accept the illness itself or its severity,
- there can be a false sense of treatment being unnecessary or an unwanted
imposition. [Kane and Garcia-Ribera, 2009]
• This leads to relapse rates in FES over 70% as early as 1 year after
diagnosis. [Emsley et al. 2012]
53

55. Fewer than 50% of patients in the Finnish healthcare system continued
treatment for the first 2 months after their initial hospitalization.
Route of administration affected relapse.
LAIs had a 64% lower relapse rate than the equivalent oral medication.
Decreased rate of hospitalisation with LAI medication compared with oral APs
in FES.
• Despite this, fewer than 10% of psychiatrists offer patients LAIs after a FES.
• However, some authors propose that LAI APs are perhaps most suited to
patients in the early stage of illness, before disease progression associated
with poor adherence occurs. [Emsley et al. 2013]
• This is because the advantages outweigh potential adverse effects.
[Rocca et al. 2013; Taylor and Ng, 2013].
55

57. • Taylor and Ng carried out a systematic review to find out whether LAI APs
should be used in early schizophrenia.
• The authors identified 10 studies: 2 cohort studies, 3 (RCTs) and 5 open
studies.
• In spite of the limited number of studies, especially RCTs, they concluded
that LAIs may be useful in the treatment of FES.
• The use of LAIs in FEPs may be more effective than oral medication in
controlling symptoms and relapse.

58. • The best rationale for using LAI APs in FES comes from the fact that
frequent relapses occur during the first years of the illness.
• Tolerability of APs is a particular concern in FES.
• Medication-naïve individuals are sensitive to APs in terms of
responsiveness as well as side effects.
• However, LAIs have a more acceptable side effect profile in comparison
with their oral APs due to lower variation in peak and trough levels.
[Taylor, 2009]
• Regarding which LAI is more suitable for FES, there is an absence of long-
term RCTs (most evidence concerns RLAI).
58

59. • There is also a lack of cost-effectiveness studies comparing LAIs with oral AP
treatments specifically focusing on FES.
• Whether we are able to alter disease trajectory to clinical and neurological
deterioration that occurs within the first 3–5 years following the onset of the
illness, e.g. the ‘critical period’, has to be studied.
• A positive answer for benefits on disease progression would provide support
to an emerging literature regarding the neuroprotective effects of SGAs.
• Psychiatrists may start considering the option of LAI APs, especially SGAs, to
more patients with first-episode or recent-onset schizophrenia in a shared
decision-making approach.
59

60. AP discontinuation after FEP: the role of LAI
formulations
• Debate exists surrounding the need to maintain or discontinue AP medication
after the FES.
• There are 10 RCT studies addressing discontinuation in cases of FEP, with
contradictory results.
• The rate of relapse in AP and placebo interventions showed heterogeneous
results.
• Some authors reported lower rates of relapse for the AP intervention (0–6%);
• Crow and colleagues found that 46% of the patients on active medication had
a psychotic relapse within 2 years.
• Chen and colleagues reported similar rates, but in 1 year.
• Boonstra and colleagues reported a higher rate of relapse on placebo
intervention in 2 years (82%) and a similar rate in 1 year (79%) was described
by Chen and colleagues. 60

61. 61

62. • Overall, studies suggest that maintenance treatment is more effective
than discontinuation, and only 1 of the 10 studies reports beneficial
effects for the discontinuation intervention. [Gaebel et al. 2002].
• Currently, there are no RCTs evaluating the efficacy of discontinuation
with LAIs.
• Interestingly, all the studies but one showed lower rates of relapse
with the AP intervention. [Crow et al. 1986]
62

63. • The question of whether the onset of psychosis associated with AP withdrawal is a
relapse of the disorder or else a new phenomenon caused by the withdrawal of APs
(‘supersensitivity psychosis’).
• The choice of the drug could prove significant.
• APs with a short half-life would be at a greater risk of developing ‘supersensitivity
psychosis’.
• The relation between onset and physiological withdrawal is clearer in drugs with a short
half-life, especially clozapine.
• The rate of relapse after discontinuation is reduced after gradual discontinuation
compared with abrupt discontinuation of Aps.
• In a meta-analysis, abrupt withdrawal was associated with 65% of relapse in six months
as opposed to only 32% with gradual withdrawal.
[Viguera et al. 1997].63

64. • Most FEP subjects will experience discontinuation 1 or 2 years after their
index episode.
• The option of LAIs may minimize both the factor that increases the risk of
supersensitivity and the risk of nonadherence, which is the major cause of
relapse.
• Supersensitivity psychosis is related with an upregulation of the dopamine D2
receptor density in the brain, as a consequence of long-term treatment with
APs.
• Clozapine has been proposed as the treatment for supersensitivity psychosis
and RLAI has also been proposed as an effective treatment.
[Gaebel et al. 2002]
• RLAI may prevent the fluctuation of dopamine D2 receptor occupancy over
time associated with the relapse of psychosis after discontinuation.

65. Long-acting injectable versus oral AP
formulations
• A meta-review of controlled clinical studies comparing oral versus LAI
FGAs, including more than 800 patients, found no differences in
relapse rates, tolerability and anticholinergic use.
• Clinical improvement was significantly more likely with LAIs.
[Adams et al. 2001].
• In fact, in a subsequent review, apart from one study, relapse was
significantly higher for patients medicated with oral APs than depots.
[Schooler, 2003].
65

67. • Studies of patients initiated or switched from oral to LAI APs reported
significant improvements not only in schizophrenia symptom control,
but also in quality of life, satisfaction and functioning.
[Kaplan et al. 2013].
• A systematic review and meta-analysis on long-term RCTs on
schizophrenia outpatients has shown that LAI versus oral APs in
improving adherence. [Leucht et al. 2011].
• The results also indicated a lower risk of relapse (10% and 30%
relative and absolute risks, respectively) and dropout for inefficacy.
67

69. Kishimoto and colleagues performed the largest meta-analysis of 21
RCTs comparing LAI versus oral APs’ efficacy for relapse prevention in
schizophrenia.
In contrast to previous meta-analysis, pooled LAIs (exception was
fluphenazine-LAI) were not superior to orals in all of the examined
relapse-related outcomes.
• Regarding LAI SGAs, a recent meta-analysis showed greater efficacy
versus placebo, but no significant differences compared with oral Aps.
[Fusar-Poli et al. 2013]
69

70. 70

71. First- versus second-generation LAI APs
• Data regarding differences between LAI FGAs and SGAs are much sparser.
• LAI FGAs have a wide range of licensed doses and are often given in too high a dose.
• Although use of higher doses is difficult to support given data available, slow rise to
steady state may explain this common practice.
• Switching studies regard mainly RLAI and have shown that patients with mild, residual
symptomatology treated with conventional depots experience significant
improvement in psychiatric and movement disorder symptoms.
• In real world settings, RLAI has been shown to significantly reduce hospitalizations
rates as compared with conventional depots.
[Grimaldi-Bensouda et al. 2012].71

72. • Patients treated with RLAI have also been shown to be much more satisfied
with themselves, their health and sleep than those on haloperidol depot.
• Patients have also reported better quality of life.
• More recently, in a 24-week open-label trial, Suzuki and Gen have shown that
switching from haloperidol decanoate to RLAI may improve cognitive function
including memory, executive function, motor processing function, and
attention.
72

73. Stroup and Mc Evoy 2016

75. Patients treated acutely with olanzapine LAI showed a similar pattern of improvement to that seen
historically with oral olanzapine.
With the exception of injection-related adverse events, the efficacy and tolerability profile of olanzapine
LAI is similar to oral olanzapine.

76. • There are no data comparing the SGAs olanzapine pamoate,
paliperidone palmitate and aripiprazol LAI with conventional FGA
depots.
76

77. Pros and Cons of Depot Preparations
77

78. 78

79. Interesting Points to Wonder and Ponder

80. Can There be Any Forensic Implications of LAI
• There are no data to suggest that a physician incurs greater liability with one route of
AP administration than with another.
• Rather than whether oral, short-term injectable, or a LAI was prescribed, the
essential medicolegal issue is the extent to which physicians meet the standard of
care by which liability is measured.
• A meaningful interaction between the physician and the patient can be documented
by including brief quotes from the patient and/or family for medicolegal purposes.
• It is difficult to discuss the benefits and risks of AP treatment with patients whose
condition involves neurocognitive deficits/ dysfunction.
• Nevertheless, physicians should always discuss treatment options and inform
patients that LAI treatment is among the best treatment approaches.
80

81. • Psychosis has been considered an important risk factor for violence.
• The UK Prisoner Cohort Study revealed that schizophrenia was associated with violence only in
the absence of treatment. [Keers et al. 2014]
• Untreated schizophrenia was associated with the emergence of persecutory delusions at
follow-up, which were associated with violence.
• Maintaining psychiatric treatment after release can substantially reduce violent recidivism
among prisoners. [Keers et al. 2014]
• LAI APs have been recommended in involuntary admission to hospital, with the goal of
increasing treatment compliance among first episode schizophrenia (FES) patients.
[Stip et al. 2011]
• It also avoids future deterioration.
• Even if it appears paradoxical, this coercive step does not seem to alter the therapeutic
alliance. 81

82. Can we initiate dual LAI?

83. Indian Perspective

84. • Patients with schizophrenia do not keep their appointment for a
detailed evaluation after initial evaluation.
• Indian studies have reported noncompliance with oral medications in
58% of the patients.
• Patients place more importance on whether they think medication is
efficacious as opposed to other factors, such as side effects.
• Psycho-educate patients with information about the efficacy of a
particular medication is also lacking.
84

85. • LAIs were prescribed to one-tenth (9.30%) of their patients in
acute phase of illness.
• One-fifth (18.42%) of patients in stabilization/stable phase.
• Fluphenazine decanoate (32.7%) was the most commonly
used LAI followed by flupenthixol decanoate (19.5%),
haloperidol decanoate (17.8%), and olanzapine pamoate
(11.1%).
• The most common reasons for starting LAI were history of
medication (100%) and treatment (80.5%) nonadherence,
followed by having frequent relapses/exacerbations of
symptoms (54.8%).

87. SUSTAIN-I Study 2017
Highlights
• First Indian survey to evaluate psychiatrists’ prescription practices in schizophrenia.
• Oral antipsychotics were the treatment of choice for acute and chronic cases.
• LAI therapy perceived to offer assurance of medication adherence and reduced
relapses.
• Owing to perceived high costs, LAIs were not preferred treatment.
• A conservative approach and sparing use of LAIs observed in India.

89. • LAIs were used as combination therapy with oral antipsychotics
(73.6%).
• Three-fifths (59%) of the participants reported that they
underuse LAI to a certain extent.
• Reasons
- the cost (55.45%),
- lack of interest of patients in receiving LAI (42.9%),
- lack of regular availability (41.3%)
- patients being scared of receiving injectables (41.2%).

90. Raghavan V, Cherubal AG, John S, Padmavati R. Comparison of cost-effectiveness of long-acting depot injection antipsychotics
and oral antipsychotics in patients with schizophrenia in a rural community in South India. Indian J Psychiatry 2020;62:747-8.

91. Raghavan V, Cherubal AG, John S, Padmavati R. Comparison of cost-effectiveness of long-acting depot injection antipsychotics
and oral antipsychotics in patients with schizophrenia in a rural community in South India. Indian J Psychiatry 2020;62:747-8.

92. Depot Preparations Available in India
92

94. • Fluphenazine decanoate- 1ml- Rs. 50- 60
• Flupenthixol decanoate- 20 mg/ ml- (40mg pack)- Rs. 150-250/-
• Haloperidol decanoate- 1 ml- Rs 40
• Zuclopenthixol decanoate- 200 mg/ml- Rs. 500- 600
• Risperidone – 2 ml- Rs. 5100 -6500
• Olanzapine Palmoate LAI (210 mg, 300 mg, 405 mg)- Rs. 1000- 1300
• Paliperidine - 100 mg- Rs. 8500- 11,500*
• Aripiprazole monohydrate- $ 456.18*

95. Conclusions
• Depot preparation is an important tool in the management of
schizophrenia.
• Its usage is limited because of perception among psychiatrists that depot
preparation should be used only when there are multiple relapses.
• There is an evidence to show that outcomes are favorable and risk of
hospitalization and relapse is reduced when depot preparation is used in
early stages of schizophrenia.
• The cost of second-generation depot preparation can be a limiting factor,
but if we consider the cost of oral pills for 1 month to depot along with
long-term risk of relapse it may seem less expensive treatment.
95

96. • The utilization of LAIs in FES to prevent cognitive decline induced by
demyelinization.
• This approach implies increasing mental health staff relations with patients to
overcome the ‘last resort treatment’ image of LAI Aps.
• Treating with LAI APs as early as possible, ideally from the first episode, can
reduce relapse, number and duration of rehospitalization and cognitive
symptoms, and improve the quality of life and functional outcomes.
• Clearly, head-to-head comparison studies between two or more LAIs are
critically needed to clarify the role of each compound in the long term
management of psychotic disorders.
96

102. • Most clinicians in India have found depot preparation to be very
useful in the management of schizophrenia.
• The choice of depot depends on tolerability, side effects, cost, and
patient’s profile.
• First-generation depots are very reasonable and effective.
• Second-generation depots are better tolerated than first generation
but cost can be a limiting factor.
102

103. • Fluphenazine depot is more effective in chronic schizophrenia.
• Haloperidol depot is more effective for controlling hostility and aggression.
• Flupenthixol depot is more effective in reducing negative symptoms.
• Olanzapine LAIs have a relatively lower propensity for EPS compared with
FGA LAIs.
• Olanzapine depot is well tolerated and cost-effective,
• Trihexyphenidyl and propranolol may be required initially to prevent
extrapyramidal side effects.
• After the patient is stabilized, they can take depot injection from a nurse or
family physician and psychiatrist can see them once in 3-4 months.
103

104. Practical Guidelines
• Length of the needle recommended is a minimum of 1.5 inches.
• Sterilize the skin before injection.
• Z-tracking technique: using the thumb, apply a shearing stress to the skin so that the skin
and subcutaneous tissue slide over the underlying muscle. Inject through the displaced
skin with a smooth action.
• If resistance is felt, it probably indicates contact with the ilium and the needle should be
withdrawn ½ “to 1” before depressing the plunger.
• As with all oily injections, it is important to ensure, by aspiration before injection, that
inadvertent intravascular injection does not occur.
• Injections should be alternated between the two sides and never be given thorough the
same puncture hole as a previous injection.
• For second-generation depot, patients’ tolerability, and safety to oral preparation of
same APs should be established.
• Risperidone depot requires cold chain.
104

106. Direction for Future Research
• Further research and understanding is needed in the art of giving LAI and in
developing new treatment strategies.
• One needs to address the optimal dose and duration of the LAI and tailor it to the
needs of the patient like when the peak level and steady states are reached, how
long to overlap with the oral APs, what to do if a dose is missed.
• Cultural variation and knowledge about fast metabolizers is very essential if
patient is neither showing response nor side effects.
• Clinicians need to update themselves regularly with the knowledge of LAI to feel
more comfortable to prescribe them.
• Long-term follow-up studies are needed in naturalistic environment to prove the
efficacy over the oral agents.
• Studies of a longer duration can add to our knowledge beyond efficacy, in terms
of symptom control and extend to relapse prevention, re-hospitalization, and
mortality.
106

107. • There is a need to increase the availability of additional LAI SGAs and to
develop more reliable methods of AP delivery.
• Longer extended release injectable formulations may be developed.
• Intranasal formulations transdermal patches, subcutaneous implants of
APs, and other long-acting devices like AP pumps may be considered since
one of the primary reasons why patients reject LAIs is the fear of needles.
• A radical change in attitude among clinicians and patients is required to
reconsider LAI APs from a new perspective: no longer medications of last
resort, but rather a potential first step to ensure treatment continuity and
maximize clinical remission.
107

108. Thank You