Antipsychotic Long Acting Injections

Dr V K SAHU

Resident Psychiatry

Headings

• Introduction

• Methods of improving outcome

• Antipsychotic Long Acting Injections (LAI)

• Pharmacology

• Individual Long Acting Antipsychotics

• Advantages & Disadvantages

• Conclusion

2

Introduction

• Schizophrenia is a major psychiatric disorder, or cluster of disorders, characterised by psychotic symptoms that alter a person's perception, thoughts, mood and ehaviour

• Continuous, long-term treatment to minimize relapse and provide clinical benefit to patients.

• Non-adherence to medication is a major risk factor for relapse and re-hospitalization.

3

Introduction - Course of Schizophrenia

4

Robinson EJ,Birchwood M. ‘Theory of mind’ skills during an acute episode of psychosis and following

recovery. Psychological Medicine 1998 Aug; 28(05): 1101-1112

Introduction

• What constitutes maintenance phase and its treatment in schizophrenia has not yet been established.

• Discontinuation and intermittent or targeted strategies are not generally recommended.

• Controversy regarding dose reduction or lower dose therapy, especially with regards to atypical antipsychotics.

5

Takeuchi H, Suzuki T, Uchida H, Watanabe K, Mimura M. Antipsychotic treatment for schizophrenia

in the maintenance phase: a systematic review of the guidelines and algorithms.. Schizophrenia

Research 2012 Feb; 134(2-3): 219-25

6

• Cognitive behavioural therapy

• Compliance therapy

• More frequent and/or longer visits

• Patient/family psycho-education

• Symptom/side effect monitoring

• Dose correction to reduce side effects

• Simplified medication regimen

• First generation long-acting

injectable antipsychotics

• Second-generation long-acting

injectable antipsychotics

Pharmacologic

al

intervention

Psychosocial and

programmatic

interventionsAdherence

LAI & Adherence

• Non-adherence may be both a cause and consequence of worsening of illness

• Long-acting injectable antipsychotic drugs can help to:

• Improve adherence

• Reduce relapse

• Lower hospitalization rates

7

Antipsychotic Long Acting Injections (LAI)

• Two groups of LAIs: First generation LAIs and Second-generation LAIs.

• First LAI – Fluphenazine Enantate- 1966.

• Second LAI- Fluphenazine decanoate.

• First of the second generation LAI –Risperidone

• Under trial LAI - iloperidone

8

LAI Classification-Delivery mechanism

9

CLASS DELIVERY AGENT

FGA OIL FLUPHENAZINE DECANOATE

HALOPERIDOL DECANOATE

FLUPENTIXOL/ZUCLOPENTHIXOL

PIPOTIAZINE PALMITATE

PERPHENAZINE DECANOATE

SGA MICROSPHERE RISEPERIDONE,ARPIPRAZOLE

CRYSTAL OLANAZAPINE PAMOATE

PALIPERIDONE PALMITATE

First-generation LAIs

• Flupentixol:• Thioxanthine antipsychotic.

• LAI is formulated as flupentixol decanoate in a low-viscosity vegetable oil (fractionated coconut oil).

• Peak plasma levels 3–7 days after IM injection

• Apparent half-life of 17 days.

• Steady-state plasma levels can be expected to be achieved after 2 months or so of regular dosing.

• In practice, plasma levels may show marked variability independent of dose changes.4

10

First-generation LAIs

• Fluphenazine:• Piperazine phenothiazine compound.

• Fluphenazine decanoate is available as an LAI in sesame oil.

• Plasma levels peak within 24 h of intramuscular injection

• Half-life is approximately 7–14 days.

• Plasma levels obtained vary up to 40-fold in patients receiving the same dose.

• Smoking significantly reduces plasma fluphenazine levels.

11

First-generation LAIs

• Haloperidol:• Butyrophenone

• Haloperidol decanoate in Sesame oil.

• Peak plasma levels are seen up to 7 days after intramuscular injection

• Plasma half-life is around 3 weeks.

• Steady-state plasma levels can be expected to be reached after 2–3 months of regular dosing.

• As with fluphenazine, clearance of haloperidol is significantly increased by smoking.

• Variation in plasma levels is smaller than oral haloperidol.

12

First-generation LAIs

• Perphenazine:• Piperazine phenothiazine

• Perphenazine decanoate in sesame oil.

• Used mainly in northern europe and scandinavia.

• After intramuscular injection, peak plasma levels are obtained in 1–7 days

• Half-life is approximately 2 weeks.

• Steady-state levels are obtained after 3 months.

• Variations in plasma levels during regular dosing are small.

• Plasma levels are directly correlated with dose.

13

First-generation LAIs

• Pipotiazine:• Piperidine Phenothiazine Antipsychotic.

• The Lai Formulation Contains Pipotiazine Palmitate In Coconut Oil.

• Provides Peak Plasma Levels After 1–2 Weeks Although No Drug Is Released For At Least 3 Days.

• Plasma Half-life Is Around 2 Weeks

• Time To Steady State Is 2 Months.

14

First-generation LAIs

• Zuclopenthixol:• Thioxanthine compound.• LAI is formulated as the decanoate ester dissolved in thin vegetable oil

(fractionated coconut oil). • Peak plasma levels of zuclopenthixol are achieved a week after

injection.• Plasma half-life has been estimated at 7.4 days and 19 days.• Shows moderate inter- and intra-individual differences in plasma levels• Marked differences b/w peak and trough plasma levels when given

every 2 weeks (peak levels more than 3 times higher than trough).• Steady-state plasma levels are achieved after around 2 months of

regular dosing

15

First Generation Antipsychotic long-acting injections : suggested doses and frequencies

Drug Licensed

injection site

Test dose

(mg)

Dose range

(mg/week)

Dosing

Interval

(weeks)

Comments

Flupentixol

decanoate

Gluteal or thigh 20 12.5-400 2-4 Maximum

licensed

dose is very

high

relative to other

LAIs

Fluphenazine

decanoate

Gluteal 12.5 6.25-50 2-5 High EPS

Haloperidol

Decanoate

Gluteal 25 12.5-75 4 High EPS

Pipothiazine

palmitate

Gluteal 25 12.5-50 4 ? Lower

incidence of

EPS (unproven)

Zuclopenthixol

decanoate

Gluteal or thigh 100 100-600 2-4 ? Slightly higher

efficacy16

Second-generation LAIs

• Risperidone:• First ‘atypical’ drug to be made

available as depot

• Contains risperidone coated in polymer to form microspheres.

• Have to be suspended in an aqueous base immediately before use.

• Stored in a fridge

• Available as doses of 25, 37.5 and 50 mg

17

• Unlike FGA-LAIs, Risperidone Long Acting Injections(RLAI) breaks down into completely natural products (CO2 and H2O)

18

Second-generation LAIs

• Risperidone injection is not suitable for patients with treatment-refractory schizophrenia.

• Peak release is at about 28 days.

• The long-acting injection also seems to be well tolerated: fewer than 10% of patients experience EPS and fewer than 6% withdrew from a long-term trial because of adverse effects.

• Doses of 25–50 mg every 2 weeks appear to be as effective as oral doses of 2–6 mg/day.

• Prolactin levels appear to reduce somewhat following a switch from oral to injectable risperidone.

• Rates of tardive dyskinesia are said to be low

19

Second-generation LAIs

• RLAI may improve the trajectory of myelination in first episode patients and have a beneficial impact on cognitive performance

20

Bartzokis G, Lu PH, Amar CP, Raven EP, Detore NR, Altshuler LL "et al". Long Acting Injection Versus Oral

Risperidone in First-Episode Schizophrenia: Differential Impact on White Matter Myelination Trajectory.

Schizophrenia Reseaarch.Supplement 2011 Oct; 132(1): 35-41.

Second-generation LAIs

21

• Paliperidone• Contains extended release

intramuscular extended-release intramuscular PaliperidonePalmitate

• Major active metabolite of risperidone: 9-hydroxyrisperidone

• Active paliperidone plasma levels are seen within a day or so, therefore co- administration of oral paliperidone or risperidone during initiation is not required

Second-generation LAIs

• Paliperidone palmitate IM does not require cold storage.

• Prefilled syringes and does not require reconstitution

• No oral supplementation is required on initiation for paliperidonepalmitate.

• No test dose is required for paliperidone palmitate (but patients should ideally be currently stabilised on or have previously responded to oral paliperidone or risperidone).

• The median time to maximum plasma concentrations is 13 days.

• Treatment with paliperidone palmitate (100 mg eq.) was efficacious and all doses tested were tolerable.

22

7. Bartzokis Gopal S1, Hough DW, Xu H, Lull JM, Gassmann-Mayer C, Remmerie BM, "et al". Efficacy and

safety of paliperidone palmitate in adult patients with acutely symptomatic schizophrenia: a randomized,

double-blind, placebo-controlled, dose-response study. International Clinical Psychopharmacology 2010

Sep; 25(5): 247-56.

Paliperidone dose and administration information

Dose Route

Initiation

Day 1

Day 8 (+/−2 days)∗ 150 mg IM Deltoid only

100 mg IM Deltoid only

Maintenance

Every month (+/− 7 days)

thereafter 50–150 mg IM∗∗ Deltoid or gluteal

23

∗The second initiation dose may be given 2 days before or after day 8 (after the first initiation dose on day 1).2 Similarly the

manufacturer recommends that patients may be given maintenance doses up to 7 days before or after the monthly time point.2

This flexibility should help to minimise the number of missed doses.

∗∗The maintenance dose is perhaps best judged by consideration of what might be a suitable dose of oral risperidone and then

giving paliperidone palmitate in an equivalent dose IM, intramuscular

Approximate dose equivalence of risperidone and paliperidone

Risperidone oral

(mg/day)

(bioavailability =

70%)

Paliperidone

oral

(mg/day)

(bioavailability =

28%)

Risperidone

LAI (Consta)

(mg/2 weeks)

Paliperidone

palmitate

(mg/month)

2 4 25 50

3 6 37.5 75

4 9 50 100

6 12 - 150

24

Second-generation LAIs

• ILOPERIDONE:• Microencapsulated depot

formulations of iloperidone and a poly-glycolide polylactideglucose star polymer.

• Under trial

25

Second-generation LAIs

26

• Olanzapine• Crystal salt made of Olanzapine & Palmoic

acid.

• Each 15 mg of Olanzapine LAI must be dissolved in 0.1 ml of water.

• Max- 3.0 ml or 450 mg Olanzapine

• 3 hr monitoring after giving injection

• Post Injection Syndrome or Post Injection Delirium Syndrome

Second-generation LAIs

27

• Post Injection Syndrome or Post Injection Delirium Syndrome:

• Mimics Olanzapine overdosage• Sedation, dizziness, slurred speech, agitation, confusion, ataxia, weakness ,

unconsciousness

• Majority occurs in first hr post-injection, progressing from mild to severe presentations

• No period of unique liability to PDSS, may occur in 1st to 66th

injection.

• Mechanism: Olanzapine LAI is highly soluble in blood compared to muscle.

• Hypothesized that direct or partial injection into vasculature or bleeding around injection site leading to direct contact of Olanzapine with blood

Peter Haddad, Tim Lambert, John Lauriello. Antipsychotic long-acting injections. Oxford: Oxford

University Press; 2011.

Second-generation LAIs

• Aipiprazole:• First dopamine D2 partial

agonist given regulatory clearance as a once-monthly injection

• Microsphere long-acting injectable (similar to RLAI)

28

Second-generation LAIs

• The most frequently reported adverse events were akathisia, insomnia and injection-site pain.

• Injection-site reactions were generally mild to moderate in severity and resolved over time.

• Extrapyramidal symptoms were reported more frequently with aripiprazole 400 mg or 300 mg prolonged-release injection than oral aripiprazole

29

Choice of antipsychotic medication

• The choice of antipsychotic medication should be made by the service user and healthcare professional together

• 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)

30

Combined antipsychotic drugs

31

• Prescribed in the short term(for example, cross-tapering while switching from one antipsychotic to another)

• In the longer term (for example, as a strategy to improve symptom control or reduce side-effects.

• With respect to longer-term use, there is no good objective evidence that combined antipsychotics (that do not include clozapine) offer any efficacy advantage over the use of a single antipsychotic.

• More harm - increased prevalence of EPS, severe EPS, increased

metabolic side-effects, paralytic ileus, grand mal seizures and prolonged QTc.

Practical issues concerning LAI administration DRUG INJEC

TION

SITE

STORAGE RECONSTITUTION & ADMINISTRATION

FGAs Gluteal Oil in vial • Z- track injection technique to avoid post-

injection leak

• Concentrates where available may

reduce injection volume

• Nodule formation with repeated injection

• Essential to rotate sites

Risperdon

e

Gluteal

or

deltoid

Powder;

special kits

• Requires cold chain storage

• Special kits & training

• Z tracking not required 32

Practical issues concerning LAI administration DRUG Injection

Site

Storage Reconstitution & administration

Paliperidone Deltoid or

Gluteal

Pre-filled

syringe kit

• Choice of needle based on weight

• Longer needle for > 90 kg

• Deltoid achieves rapid uptake

• Z-tracking not required

Olanzapine Gluteal Powder,

special kits

• Special kits & training required

• Large volume at top doses

• Z- tracking not required

• 3 hr observation in health care due to possibility of Post-

injection syndrome

Aripiprazole Gluteal Pre-filled

dual

chamber

syringe

• Not indicated for the treatment of people with dementia-

related psychosis

• Z-tracking not required

33

Equivalence of specific SGAs in oral & LAI formSGA-LAI Drug Target oral equivalent dose LAI Dose & Frequency

Risperidone < 3 mg oral 25 mg 2 – weekly

3 mg to 5 mg oral 37.5 mg 2- weekly

> 5 mg oral 50 mg 2 -weekly

Paliperidone(a) 6 mg 117 mg 4 -weekly

9 mg 156 mg 4- weekly

Olanzapine 10 mg 150 mg 2 -weekly

300 mg 4- hrly

15 mg 210 mg 2 -weekly

405 mg 4- weekly

20 mg 300 mg 2 - weekly

No 4 weekly equivalent

34(a)- 39 mg, 78 mg, 117 mg, 156 mg, 234 mg equivalent to 25 mg, 50 mg, 75 mg, 100 mg &

150 mg of marketed Paliperidone

Schizophrenia Guideline Relation to non-adherence and/or relapse.

Consider an LAI if :

LAI indicated if patient

expresses preference

for this treatment

American Psychiatric

Association(Lehman et al. 2004a)

Partial to full non-adherence leading to recurrent

relapses

-

Canadaian Clinical Practise

Guidelines (Canadian Psychiatric

Association 2005

Non-adherence in multi-episode patients or those

with persistent positive symptoms

-

NICE (National Institute of Clinical

Excellence) 2009

Avoidant of covert non-adherence is a priority Yes

Patient Outcomes Research

Team(PORT) Recommendations

(Lehman et al. 2004b)

Frequent Relapses on oral medication or a history

of problems with poor adherence on oral medication

Yes

RANZAP (Royal Australian & New

Zealand College of Psychiatrists)

2005

Despite psychosocial adherence interventions a

patient repeatedly fails to adhere to necessary

medication and relapses frequently

Yes

Texas Medication Algorithm (Miller et

al. 2004)

Inadequate adherence at any stage -

Peter Haddad, Tim Lambert, John Lauriello. Antipsychotic long-acting injections. Oxford: Oxford University

Press; 201135

Advice on prescribing long-acting injections of antipsychotic drugs• For FGAs, give a test dose. For SGAs, test doses are not

required (less propensity to cause EPS and aqueous base not known to be allergenic).

• Begin with the lowest therapeutic dose.

• Administer at the longest possible licensed interval.

• Adjust doses only after an adequate period of assessment. Doses may be reduced if adverse effects occur, but should be increased only after careful assessment over at least 1 month, preferably longer.

• Not recommended for those who are antipsychotic-naive

36

Reducing dose of depots

• If it has not already been done, oral antipsychotic medication should be discontinued first.

• The interval between injections should be increased to up to 4 weeks before decreasing the dose given each time. Note: not with risperidone.

• The dose should be reduced by no more than a third at any one time. Note: special considerations apply to risperidone.

• Decrements should, if possible, be made no more frequently than every 3 months,preferably every 6 months.

• Discontinuation should be seen as the endpoint of the above process

37

LAI FGA and LAI SGA Indications according to the DSM-IV-TR criteria

38

Pierre ML, Mocrane A, Philippe C, Sebastien G, Sylvie L,Ludovic, Guidelines for the use and management of

long-acting injectable antipsychotics in serious mental illness, BMC Psychiatry 2013,(13) 340

LAI FGA LAI SGA

1st Line Treatment

Schizophrenia

Delusional disorder

Schizoaffective disorder

2nd Line Treatment

Schizophrenia

Delusional disorder

Schizoaffective disorder

Personality Disorder

Bipolar disorder

Personality disorder

Use of LAI FGA and LAI SGA according to the period of the illness

LAI FGA LAI SGA

Schizophrenia

LAI FGA are not recommended in

the initial phase of the disorder

Very early introduction of LAI SGA

is recommended (eventually from

the 1st psychotic episode).

LAI FGA can be used during the

maintenance treatment in the

case of the efficacy of the oral

form and when the benefit/risk

ratio is considered as satisfactory

It is recommended that an LAI SGA

be introduced from the 1st

recurrent psychotic episode (if the

patient was not treated with an LAI

antipsychotic).

Biploar Disorder

LAI FGA are not recommended LAI SGA are not recommended in

the initial phase of bipolar disorder.

39Pierre ML, Mocrane A, Philippe C, Sebastien G, Sylvie L,Ludovic, Guidelines for the use and management of

long-acting injectable antipsychotics in serious mental illness, BMC Psychiatry 2013,(13) 340

Indications of LAI FGA and LAI SGA according to clinical characteristics of the illness

Schizophrenia Bipolar disorder

1st Line LAI FGA or

LAI SGA

• Frequent relapses

• Non-adherence

(partial/full)

• Hazard risk for others

• Low insight

• Patient preference

• Positive depot

experienced

1st Line

LAI SGA

• Non-adherence (partial/full)

• Patient preference

• Positive depot experienced

LAI SGA • Cognitive deficits Social

isolation

2nd Line LAI FGA or

SGA

Positive symptoms 2nd Line • BD I

• Manic polarity

• Rapid cycler

• Hazard risk for others

• Low insight

LAI SGA • Negative symptoms

• Suicidal risk

40

Benefit/risk ratio for LAI FGA and LAI SGA in Schizophrenia

Prevention of psychotic

recurrence

1st Line of Treatment Risperidone LAI

2nd Line of Treatment Olanzapine pamoate

Haloperidol decanoate

Zuclopenthixol decanoate

Flupentixol decanoate

Fluphenazine decanoate

Pipotiazine palmitate

41

Pierre ML, Mocrane A, Philippe C, Sebastien G, Sylvie L,Ludovic, Guidelines for the use and management

of long-acting injectable antipsychotics in serious mental illness, BMC Psychiatry 2013,(13) 340

Benefit/risk ratio for LAI FGA and LAI SGA in Bipolar disorder

Prevention of manic

recurrence

Prevention of

depressive

recurrence

1st Line Treatment - -

2nd Line Treatment In monotherapy or in

combination

with a mood stabilizer

Always in combination

with a mood stabilizer

Risperidone LAI Risperidone LAI

Olanzapine pamoate Olanzapine pamoate

42

Pierre ML, Mocrane A, Philippe C, Sebastien G, Sylvie L,Ludovic, Guidelines for the use and

management of long-acting injectable antipsychotics in serious mental illness, BMC Psychiatry

2013,(13) 340

Disadvantages of LAI over oral antipsychotics1. Understanding the pharmacokinetics & dosing require specific LAI

knowledge.i. Delayed time until steady state is reachedii. Clinical improvement may be delayed after dose increaseiii. Elimination may take weeks to months

2. Adverse effects may persist after stopping/reducing dose

3. Less scope of dynamic titration.

4. Injection related adverse effects e.g. pain, nodules

5. Some patient rehards LAI as indicating a lack of control or autonomy

6. Organised community system to deliver LAIs

7. LAI storage, reconstitution & administration may require special precautions, &/or training

8. SGA-LAI have high acquisition costs

Peter Haddad, Tim Lambert, John Lauriello. Antipsychotic long-acting injections. Oxford: Oxford

University Press; 201143

Advantages of depot antipsychotics over oral antipsychotic1. Improved treatment adherence, overt non-adherence can be addressed

2. Easier early detection of relapse, improved relapse prevention and reduced rehospitalisation rates

3. Enhanced consistency between the drug prescription and drug delivery

4. More predictable and stable serum concentrations

5. Less variability between patients in steadystate blood levels for a given dose

6. Lowest effective dose principle more safely achieved with depots (step-wise reduction)

7. Reduced risk of accidental or deliberate selfpoisoning (overdose)

8. Less risk of overdose

9. Bypasses pharmacokinetic hurdeles of absorption & first pass hepatic elimination

Thomas R.E. Barnes. Why aren't depot antipsychotics prescribed more often and what can be

done about it?. Advances In Psychiatric Treatment 2005; (11): 211-213.44

Tackling myths about depot drugs

1. Risk of neuroleptic malignant syndrome is not higher for depot than oral drugs

2. No evidence to suggest that neuroleptic malignant syndrome is a contraindication for subsequent depot use

3. For the same drug, the risk of tardive dyskinesia is not higher for depot than oral formulations

4. Patients already on depot like this formulation and many prefer depot to oral drugs

5. Clinicians perceive a stigma to be associated with depots but this may be based on the worst characteristics of typical drugs (e.g. unacceptable side-effects) rather than on intramuscular long-acting injections per se

6. Most nursing staff are aware of the benefits of depots but their training experiences and pressure of time may adversely affect systematic monitoring of potential side-effects

45

Thomas R.E. Barnes. Why aren't depot antipsychotics prescribed more often and what can be done

about it?. Advances In Psychiatric Treatment 2005; (11): 211-213.

Metanalysis of LAI efficacy

• Kirson NY et al:

• Comparative effectiveness of antipsychotic formulations is sensitive to research design

• Depot formulations displayed significant advantages in nonrandomized observational studies. In RCTs no difference was observed

• Lafeuille MH et al:

• Meta-analysis, including studies with both interventional and non-interventional designs and using meta-regressions

• LAIs are associated with higher reductions in hospitalization rates for schizophrenia patients compared to oral antipsychotics.

46

Lafeuille MH, Dean J, Carter V, Duh MS, Fastenau J, Dirani R, Lefebvre P. Systematic review of long-acting

injectables versus oral atypical antipsychotics on hospitalization in schizophrenia. Current Medical Research

and Opinion 2014; 30(08): 1643-1655.

Kirson NY, Weiden PJ, Yermakov S, Huang W, Samuelson T, Offord SJ "et al". Efficacy and effectiveness of

depot versus oral antipsychotics in schizophrenia: synthesizing results across different research designs. The

Journal of Clinical Psychiatry 2013 Jun; 74(06): 568-75

Conclusion

• When selecting a specific LAI, consider class similarities and individual antipsychotic differences.

• Individualize the dose and dosing interval based on patient response, peak-related adverse effects (time to peak is approximately 5 half-lives for most drugs), and possible reduced symptom control at the end of the dosing interval

• Although some LAIs are expensive, they potentially reduce the financial burden of schizophrenia and improve quality of life.

• Do not rule out first-generation LAIs.

47

Conclusion

• Consider a loading dose strategy to minimize the time a patient has to take an oral and LAI antipsychotic combination.

• If antipsychotic polypharmacy is necessary, document your rationale.

• Keep other reasons for non-adherence in mind & intervene accordingly.

48

References1. Peter Haddad, Tim Lambert, John Lauriello. Antipsychotic long-acting injections. Oxford:

Oxford University Press; 2011.

2. Stephen M Stahl. Antipsychotic agents. In: (eds.)Stahl's essential psychopharmacology. 4th ed. Cambridge: Cambridge; 2013. p129-236

3. Thomas R.E. Barnes. Why aren't depot antipsychotics prescribed more often and what can be done about it?. Advances In Psychiatric Treatment 2005; (11): 211-213.

4. Maxine X. Patel and Anthony S. David. Why aren’t depot antipsychotics prescribed more often and what can be done about it?. Advances in Psychiatric Treatment 2005; (11): 203-211.

5. John M. Kane, Carlos Garcia-Ribera. Clinical guideline recommendations for antipsychotic long-acting injections. The British Journal of Psychiatry.Supplement 2009 Nov; (195): s63–s67.

6. Bartzokis G, Lu PH, Amar CP, Raven EP, Detore NR, Altshuler LL "et al". Long Acting Injection Versus Oral Risperidone in First-Episode Schizophrenia: Differential Impact on White Matter Myelination Trajectory. Schizophrenia Research.2011 Oct; 132(1): 35-41.

49

7. Bartzokis Gopal S1, Hough DW, Xu H, Lull JM, Gassmann-Mayer C, Remmerie BM, "et al". Efficacy and safety of paliperidone palmitate in adult patients with acutely symptomatic schizophrenia: a randomized, double-blind, placebo-controlled, dose-response study. International Clinical Psychopharmacology 2010 Sep; 25(5): 247-56.

8. Robinson EJ,Birchwood M. ‘Theory of mind’ skills during an acute episode of psychosis and following recovery. Psychological Medicine 1998 Aug; 28(05): 1101-1112

9. Lafeuille MH, Dean J, Carter V, Duh MS, Fastenau J, Dirani R, Lefebvre P. Systematic review of long-acting injectables versus oral atypical antipsychotics on hospitalization in schizophrenia. Current Medical Research and Opinion 2014; 30(08): 1643-1655.

10. Pierre ML, Mocrane A, Philippe C, Sebastien G, Sylvie L,Ludovic, Guidelines for the use and management of long-acting injectable antipsychotics in serious mental illness, BMC Psychiatry 2013,(13) 340

50