Iloperidone is an atypical antipsychotic that acts through several receptor mechanisms. It exhibits high affinity for dopamine D2, serotonin 5-HT2A, alpha1, and alpha2C receptors. It also shows moderate affinity for serotonin 5-HT1A, 5-HT2C, 5-HT7, dopamine D3, and histamine H1 receptors. Through its receptor binding profile, iloperidone is effective in treating positive and negative symptoms as well as improving cognition and reducing anxiety. Its mixed receptor actions contribute to its favorable side effect profile with low risk of extrapyramidal symptoms and metabolic issues.

1. ROLE OF ILOPERIDONE IN
PSYCHIATRIC DISORDERS
PRESENTOR
DR. ANANT KUMAR RATHI
1st YEAR RESIDENT
GUIDE
DR. D. K. SHARMA
PROF. & HEAD, DEPTT. OF PSYCHIATRY
GOVT. MEDICAL COLLEGE, KOTA

2. Neurophysiology of psychotic symptoms

3. I. Positive II. Negative
Symptoms Symptoms
- Delusions - affective flattening
- Hallucinations - alogia
- disorganised - avolition
speech - anhedonia
- catatonia
Social/Occupational
Dysfunction
- work
- interpersonal relationship
- self care
III. Cognitive symptoms IV. Affective symptoms
- attention - dysphoria
- suicidality
- memory
- hopelessness
- executive functions

4. Typical (first-generation) antipsychotic drugs – mechanism of action
Potential worsening Extrapyramidal
of 'negative' signs
symptoms
(due to blockade of the
(due to D2 receptor
already decreased
blockade in nigrostriatal
dopaminergic transmission
pathway)
in the mesocortical
pathway)
Striatum
D2
Frontal
Cortex
VTA
Limbic
System
Substantia Raphe
Nigra Nuclei
Serotonin secreted by
serotonergic neurons
causes 5-HT2 receptor
Improved 'positive' signs stimulation and
(due to blockade of excessive subsequent inhibiton
dopaminergic transmission in of mesocortical
dopaminergic
the mesolimbic pathway)
neurons

5. Atypical (second-generation) antipsychotic drugs – mechanism of action

6. What makes an antipsychotic atypical
• Clinical perspective:-
– Low EPS
– Good for negative symptoms
• Pharmacological perspective:-
(I) Serotonin Dopamine Antagonism (SDA)
(II) D2 antagonism with tendency for rapid dissociation
(III) D2 partial agonism (DPA)
(IV) Serotonin partial agonism (SGA) at 5HT1A

7. I. Serotonin Dopamine Antagonism (SDA)
• Serotonin Receptors
• Pre-synaptic receptors:- 5HT1A, 5HT1B/D
• Post synaptic receptors:- 5HT1A, 5HT1B/D, 5HT2A, 5HT2C,
5HT3, 5HT4, 5HT5, 5HT6, 5HT7
• 5HT1B/D :- Terminal autoreceptor located on axon terminals
Occupancy of these receptors inhibit further 5HT
release
• 5HT1A :- Somatodendritic autoreceptor located in cell
dendrite and cell body
Occupancy of these receptors cause slowing of
neuronal impulse flow

8. • 5HT1A receptor inhibit cortical pyramidal neurons :-
Regulate hormones, cognition, anxiety & depression
• 5HT2A receptor excite cortical pyramidal neurons :- Enhance
glutamate release and inhibit dopamine release, thus playing
role in sleep & hallucinations
• 5HT2C receptor regulate both dopamine and epinephrine :-
Play role in obesity, mood & cognition
• 5HT6 receptor regulate release of BDNF which in turn
regulate formation of long term memory
• 5HT7 receptor may be related to circadian rhythm

9. 5HT1A receptor :- Dopamine release
Glutamate release
5HT2A receptor :- Dopamine release
Glutamate release
5HT2A antagonism makes antipsychotic atypical
5HT2A receptor brake, on dopamine release is disrupted
by 5HT2A antagonist thus increasing dopamine release in
prefrontal cortex
5HT2A antagonism reduces EPS
5HT2A antagonism reduces negative symptoms

10. • 5HT2A antagonism may improve positive symptoms
• When 5HT2A antagonist bind to cortical neuron,
glutamate release is reduced and ultimately dopamine
release is reduced (control of positive symptoms)
• Ideal treatment of schizophrenia :-
• Drug which fully saturate 5HT2A receptors in prefrontal
cortex
• Enough blockade of D2 receptors in mesolimbic area to
reduce positive symptoms but not to abolish reward
• Thus SDA tune the dopamine output in malfunctioning
areas of brain

11. II. Rapid dissociation from D2 receptors
• Hit & Run binding :- Atypical antipsychotics have ability to
rapidly dissociate from D2 receptors
• Thus relieve positive symptoms without causing :-
– EPS
– Hyperprolactinemia
– Worsening of negative symptoms
III. D2 Partial Agonism (DPA)
• Goldilocks drugs :- Intrinsic ability to bind D2 receptors in
a manner that balance just right between full agonism and
complete antagonism
• So D2 activity sufficient enough to control positive
symptoms while avoiding EPS

12. IV. 5HT1A Partial Agonism (SPA)
5HT1A receptor :-
Dopamine release :-
Improves negative, cognitive & affective symptoms
Improves EPS
Reduces hyperprolactinemia
Glutamate release :-
Reduces positive symptoms (hallucinations)

13. Cardiovascular risk & Antipsychotics
• H1 Histaminic receptor
Weight gain
• 5HT2C receptor
• Some antipsychotics can elevates fasting triglycerides levels and
cause insulin resistance
Antipsychotic Risk of weight Dyslipidemia Cardiometabolic
gain Diabetes risk risk
CATIE
Clozapine +++ Not done
Olanzapine +++ Definite risk
Risperidone ++ Intermediate
Quetiapine ++ Definite risk
Ziprasidone +/-- Low risk Low risk
Aripiprazole +/-- Not done Low risk
Amisulpride Possibly low
Bifeprunox Possibly low

14. Premature death
loss of 20-30 yrs
of normal life
Metabolic
Highway
Diabetes Cardiovasc
ular events
Beta cell
Pre
failure
diabetes
Insulin
resistance
Obesity Pancreas
Increased Hyperinsulinemia
BMI
Triglycerides
Increased
appetite
Beware
Cardiovasc
ular risk
Weight ahead
gain

15. • Metabolic monitoring kit
Baseline Visit 1 Visit 2
Wt./BMI
Fasting TGs
Fasting glucose
Blood pressure
Insulin resistance
Aging, Genes Life style, Diet Choice of antipsychotic
No option Modest chance of success Most manageable option

16. Sedation and antipsychotics
Sedation Somnolence
M1 H1 Alpha H1 Alpha
binding binding binding binding binding
Cognitive functioning
Sleepiness
Attention
Drowsiness
Memory
Need to day time
Coordination
sleep
Psychomotor activity
Compromise overall
patient functional
outcome

17. What constitute an ideal Antipsychotic
Mood-stabilizing
Efficacious for properties
Positive & negative Low EPS, TD
symptoms
Cognitive benefits Ideal Weight Neutral
Antipsychotic
Improved No adverse
Function and Long-term health
Quality of life Consequences
Affordable

18. Limitations of Current Atypical
Antipsychotics
•Gaps in efficacy remain
– Cognitive function
– Negative symptoms
– Depressive symptoms – Significant weight gain
– Significant risk of
hyperglycemia and type 2
diabetes mellitus
•Improved motor side effects – Altered lipid profile
but now different adverse – Cardiac effects
effects for some atypicals • Hypotension
with long-term • QTc prolongation
consequences: – Hyperprolactinemia

19. Iloperidone Pharmacology
• A benzisoxazole drug,
structurally similar to
risperidone
• No tricyclic structure
like olanzapine,
quetiapine
• Not a derivative or
metabolite of other
atypical antipsychotics

20. Pharmacokinetics
• Oral and injectable formulations
• Well absorbed in GI Tract
• Not affected by food or smoking
• Bioavailability is 96%
• Peak plasma conc. within 2 to 4 hrs.
• Plasma protein binding is about 95%
• Half-life 18-26 h (EM); 31-37 h (PM)
• Steady state conc. reaches in 3 - 4 days

21. Metabolism:- Hepatic metabolism
Involving two P450 isozymes CYT3A4 & CYT2D6
Two predominant metabolites P95 & P88
Excreted in bile and feces

22. Iloperidone- mechanism of action
(D2/5-HT2A)
• Exhibits mixed
D2/5-HT2A
Iloperidone
antagonism
• Resolves
– Positive symptoms
– Negative symptoms
– Anxiety
It is proposed that the efficacy of iloperidone is mediated
through a combination of dopamine type 2 (D2) and
serotonin type 2 (5-HT2A) antagonisms
Expert Opin Investig Drugs 2008; 17(1): 61-75

23. D2 antagonism in mesolimbic pathway
(1) nigrostriatal pathway
(2) mesolimbic pathway
(3) mesocortical pathway
(4) tuberoinfundibular pathway
• D2 antagonism resolves the
positive symptoms
1. Stahl SM. Essential Psychopharmacology. 2nd Ed. New York, NY: Cambridge University Press; 2000
2. Primary Care Companion J Clin Psychiatry 2003; 5[suppl 3]: 9–13)

24. 5-HT2A antagonism in mesocortical pathway
(1) nigrostriatal pathway
(2) mesolimbic pathway
(3) mesocortical pathway
(4) tuberoinfundibular pathway
• 5HT2A antagonism increases DA release and ameliorates negative
symptoms, cognitive symptoms and anxiety
1. Stahl SM. Essential Psychopharmacology. 2nd Ed. New York, NY: Cambridge University Press; 2000
2. Eur J Pharmacol. 1995 Feb 6;273(3):273-9
3. Psychopharmacology (Berl). 1998 Feb;135(4):383-91

25. Iloperidone- mechanism of action (D3)
• Exhibits D3
antagonism
Iloperidone • Resolves
– Positive symptoms
May also be helpful in
substance abuse
aggression
1. Expert Opin Investig Drugs 2008; 17(1): 61-75
2. Int J Neuropsychopharmacol. 2010 Mar;13(2):181-90
3. Psychopharmacology (Berl). 1999 May;144(1):90-4

26. Iloperidone- mechanism of action (5-HT7)
• Iloperidone exhibits
5-HT7 antagonism
• Blockade of 5-HT7
Iloperidone receptors partially
modulates
glutaminergic and
dopaminergic
function and could
be clinically useful
for the treatment of
positive symptoms
of schizophrenia
Behavioural pharmacology 2008; 19(2): 153-9

27. Iloperidone- mechanism of action (α1)
• Iloperidone
exhibits α1
receptor
antagonism
Iloperidone
• Blockade of α1
adrenoceptors
helps to protect
PFC cognitive
function
Psychopharmacology 2004. 174(1): 25-31

28. α1 receptors in schizophrenia
Patients
Patients taking α1 antagonist
High levels of
norepinephrine
Blockage of α1 receptor
by the α1 antagonist
Activates protein kinase C
(Pathway for etiology of
schizophrenia)
Blocks activation of
protein kinase C signaling
Impaired pre-frontal
cognitive function
Protects pre-frontal cognitive
functioning
• α1 receptor contribute to anti-psychotic activity via
protection of pre-frontal cortex cognitive function by
blocking the activation of protein kinase C signaling
Psychopharmacology 2004. 174(1): 25-31

29. Iloperidone- mechanism of action (α2C)
• Iloperidone exhibits
α2C antagonism
• Norepinephrine has
marked influences
on PFC cognitive
α 2C functioning
Iloperidone
• Blockade of the α2C
receptor improve
cognition and
attention by
enhancing
catecholamine and
dopamine release
1. Expert Opin Investig Drugs 2008; 17(1): 61-75
2. Psychopharmacology 2004. 174(1): 25-31

30. Iloperidone- mechanism of action (5-HT2C)
• Iloperidone exhibits
5HT2C receptors
antagonism
α 2C • 5-HT2C receptors
Iloperidone antagonism resolves
negative symptoms
and anxiety by
increasing DA release
in mesocortical
pathway
1. Expert Opin Investig Drugs 2008; 17(1): 61-75
2. Synapse 2005; 55(4): 242-51
3. Genes Brain Behav 2007; 6(5): 491-6

31. 5-HT2C receptors in anxiety
Sensory information Iloperidone blocks
5-HT2C receptor
Processed in
amygdala
5-HT2C receptor activation.
Release of corticotrophin- Blunting of amygdala
releasing hormone corticotropin-releasing
hormone neuronal activation
Neuronal activation in
prefrontal cortex
No anxiety
Execution function
Anxiety
• 5-HT2C receptor antagonists alleviate anxiety via
blunting of corticotropin-releasing hormone neuronal
activation in pre-frontal cortex
Genes Brain Behav 2007; 6(5): 491-6

32. Iloperidone- mechanism of action (5-HT1A)
• Iloperidone exhibits low 5-
HT1A receptors partial
agonism
α 2C
• Enhances cognition by
Iloperidone
increasing the extra-cellular
glutamate concentration
• Reduces depression by
increasing the dopamine
release in the mPFC by
postsynaptic activation of the
5-HT1A receptors
1. BMC Psychiatry. 2009;9: 71
2. Behav Brain Res 2008; 195(1): 54-77
3. Eur J Pharmacol. 1987; 134(3): 265-74

33. 5-HT1A receptor in cognition
Activation of 5-HT1A receptor
Inhibit glutamate
Pathological alterations in the
neuronal circuitry of the dorsolateral
prefrontal cortex
Resolves depression by
Impaired cognition, learning, and
memory by interfering increasing the dopamine
with memory-encoding mechanisms release in the mPFC by
postsynaptic activation of
the 5-HT1A receptors
1. BMC Psychiatry. 2009;9: 71
2. Behav Brain Res 2008; 195(1): 54-77
3. Eur J Pharmacol. 1987; 134(3): 265-74

34. Iloperidone binding affinity - Summary
Affinity Receptor Clinical advantage
High 5-HT2A Improves negative symptoms and reduces anxiety
D2 Improves positive symptoms
D3 Improves positive symptoms. Reduces substance abuse
Moderate 5-HT7 Improves positive symptoms
α1 Improves cognition & induces postural hypotension
α2C Improves attention and cognition
5-HT6 Improves cognition
5-HT2C Improves negative symptoms and anxiety
Low 5-HT1A Improves cognition and resolves depression
Expert Opin. Investig. Drugs 2008; 17(1): 61-75.

35. Iloper
idone

36. Clinical studies of Iloperidone
EFFICACY AND SAFETY STUDIED IN MORE THAN 3000 PATIENTS
3000 -To evaluate the efficacy and safety of three fixed doses of iloperidone (4, 8
• Efficacy and 12 mg/day) given twice daily for 42 days compared with placebo,
in schizophrenia and schizoaffective patients with acute exacerbation
studied
in > 3000 3001- To evaluate the efficacy and safety of iloperidone (4 -16 mg/day) given,
patients 3002 twice daily for up to 52 weeks compared with haloperidol (5 - 20 mg/day),
3003 in schizophrenia and schizoaffective patients
• 4 short- 3004 To evaluate the efficacy and safety of two dose ranges of iloperidone (4 - 8
and 10 - 16 mg/day) given twice daily for 42 days compared with placebo,
term (4-6 in schizophrenia and schizoaffective patients with acute exacerbation
weeks)
and 3 3005 To evaluate the efficacy and safety of two dose ranges of iloperidone
long- (12 - 16 and 20 - 24 mg/day) given twice daily for 42 days compared with
placebo, in schizophrenia and schizoaffective patients ‘with
term (52 acute exacerbation
weeks)
studies 3101 To evaluate the efficacy and safety of a fixed dose of iloperidone
(24 mg/day) given twice daily for 28 days compared with placebo, in
schizophrenia patients with acute exacerbation
Expert Rev Neurother 2009; 9(12): 1727-1740

37. BETTER CONTROL OF OVERALL SYMPTOMS WITHIN 6 WEEKS
Iloperidone versus placebo - Improved total symptoms as measured by PANSS
4 week, db, pc, ac
*P<0.01 *
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
1 1 2 2 4 4 6 6 8 8 10 10 12 12

38. BETTER CONTROL OF OVERALL SYMPTOMS WITHIN 6 WEEKS
Iloperidone versus placebo - Improved total symptoms as measured by BPRS
6 week, db, r, pc, ac *
*P=0.033 **
**P=0.005
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7
1 1 2 2 4 4 6 6 8 8 10 10 12 12

39. Efficacy – Iloperidone versus haloperidol and risperidone
• Source: Pooled data from 3 prospective, MC studies
• N= 1644
• Study duration= 6 weeks
• Drugs dosages
– Iloperidone (4-24 mg/day)
– Haloperidol (15 mg/day)
– Risperidone (4-8 mg/day)
• Primary Efficacy in study 1: Change from baseline to end-
point in positive and negative syndrome scale total scores
(PANSS)
• Primary Efficacy in study 2 and 3: Change from baseline to
end-point in positive and negative syndrome scale-derived
Psychiatric Rating Scale Score (BPRS)
J Clin Psychopharmacol 2008; 28: S4–S11

40. Efficacy – Iloperidone versus haloperidol and risperidone
(BPRS and PANSS-T scores)
• Iloperidone shows comparable efficacy with haloperidol, risperidone
0
-2
-4
-3.6 -3.7 -3.6
-6
-5.8
-6.3
-8 -7.1 -7.3
Iloperidone
-10 -8.9 -8.4
Haloperidol
-10
-12 -11.4 Risperidone
-11.9
-14
-16
-18 -16.5
-20 -18.8-18.9
PANSS-T PANSS-P PANSS-N PANSS-GP BPRS
Iloperidone -16.5 -5.8 -3.6 -7.3 -10
Haloperidol -18.8 -6.3 -3.7 -8.9 -11.4
Risperidone -18.9 -7.1 -3.6 -8.4 -11.9
J Clin Psychopharmacol 2008; 28: S4–S11

41. Efficacy - Iloperidone versus Ziprasidone
• Study: R, PC, MC
• N=606
• Drug dosage:
– Iloperidone- 24 mg/ day or
– Ziprasidone 160 mg/ day or
– Placebo
• Duration- 4 weeks
• Primary Efficacy: Change
from baseline to end-point in • Efficacy of
positive and negative iloperidone
syndrome scale total scores was
(PANSS) comparable to
that of
ziprasidone

42. Long term efficacy - Iloperidone versus Haloperidol
• Study- R, MC, DB
maintenance phases
• N= 489
• Drug dosage:
• Iloperidone 4-16 mg/ day
or
• Haloperidol 5-20 mg/ day
• Duration- 52 weeks • Time to relapse was
• The primary efficacy: Time to similar in iloperidone
relapse, defined as a 25% or and haloperidol
more increase in PANSS total groups as observed
score
by hazards analysis of
time to relapse

43. Long term efficacy - Iloperidone versus haloperidol
(reductions in PANSS-T)
• Similar reductions in PANSS-T and other PANSS-derived
scales was observed in iloperidone and haloperidol groups
confirming the equivalent efficacies in the long-term study
Expert Rev neurother 2009; 9(12): 1727-41

44. Safety and tolerability

45. Discontinuation rates due to adverse events
were similar to placebo
• Data based on pooled data from 4 placebo-controlled, 4- or
6 week , fixed or flexible-dose studies.
Placebo
Iloperidone ≥ 10 mg/day
(N=587)
(N=874)
5% 5%
• The type of adverse events that led to discontinuation were
similar for the iloperidone and placebo-treated patients

46. Safety – Iloperidone versus haloperidol and risperidone
(discontinuation due to AEs)
• More patients
discontinued Adverse events leading to discontinuation of
medicines
medications in the 8 7.6
risperidone and 7
6
6.2
haloperidol group 5
4
3.9
Iloperidone
Risperidone
compared to that in 3
2
Haloperidol
the iloperidone 1
0
group due to adverse Pts with ≥ 1 AE leading to discontinuation (%)
events
J Clin Psychopharmacol 2008; 28: S4–S11

47. Safety – Iloperidone versus haloperidol and risperidone
(overall AEs)
• Less adverse events were found in the iloperidone group
compared to risperidone and haloperidol groups
J Clin Psychopharmacol 2008; 28: S4–S11

48. Safety – Iloperidone versus ziprasidone (overall AEs)
• Iloperidone was associated with lower incidence of
adverse events such as sedation, somnolence, EPS,
akathisia, agitation and restlessness
J Clin Psychopharmacol 2008; 28: (S20-S28)

49. Safety:- Patients taking Iloperidone experienced an
incidence of EPS similar to placebo in CTs .
Does not increase with increased dose
Data based on pooled data from 4 placebo-controlled, 4- or 6 week , fixed or flexible-dose studies

50. Safety – Iloperidone versus placebo (EPS)
• EPS events observed with iloperidone were similar to that
of placebo
Vanda Pharaceuticals inc. FanaptTM (iloperidone) tablets:US prescribing information (online).
Available from URL: http://www.fanapt.com/fanapt-pi-may09.pdf

51. Safety – Iloperidone versus ziprasidone (akathisia)
• Significantly less incidence of akathisia was
reflected in BAS total score (p<0.05) with
iloperidone as compared to ziprasidone
J Clin Psychopharmacol 2008; 28: (S20-S28)

52. Safety – Iloperidone versus risperidone and placebo
(Worsening BAS score)
• Worsening of BAS score was observed more in
risperidone and placebo group than in iloperidone
J Clin Psychopharmacol 2008; 28: S12–S19

53. Safety – Iloperidone versus haloperidol and risperidone
(EPS rating)
• Significant
improvement in the
EPS rating on ESRS
subscale score was
observed in the
iloperidone groups
(p<0.05)
• No significant change
was seen in
risperidone group
• Haloperidol was
associated with
significant worsening
(p<0.05)
J Clin Psychopharmacol 2008; 28: S4–S11

54. Safety – Iloperidone versus haloperidol and risperidone
(parkinsonism and akathisia)
• Parkinsonism and akathisia items showed significant
improvement from baseline in the iloperidone group
• No difference was observed for risperidone
• Scores significantly worsened in haloperidol group
J Clin Psychopharmacol 2008; 28: S4–S11

55. Safety - Iloperidone versus haloperidol and risperidone
(dyskinesia)
• Dyskinesia items showed significant improvement from
baseline in the iloperidone group
0.4 0.2 0.2
0.2 0.1 0.2
0
-0.2 -0.1-0.1
-0.4 -0.2 -0.2
-0.6 -0.4
Iloperidone
Dyskinesia Dyskinesia Trunk limb
Risperidone
Haloperidol
physician dyskinesia
total

56. Long term safety – Iloperidone versus haloperidol
(overall AEs)
Adverse events (% of patients)
15 14.4
12.7 12.7
10
6.8
5.1 5.9
4.9 4 3.8 3.5
5 2.2
0.8
0
Iloperidone Haloperidol
• Iloperidone was associated with lower incidence of adverse
events such as tremor, muscle rigidity, akathisia, restlessness,
constipation and EPS in the long term follow up period
J Clin Psychopharmacol 2008;28: S29–S35)

57. Schizophrenia : Diabetes Mellitus
• Possible additional increased risk with atypical
agents*
– Increased weight gain
– Estimated DM rates on atypical agents;*
Clozapine 10%-37% Risperidone 5%-8%
Olanzapine 6%-17% Quetiapine 8%-12%
• Higher prevalence with prospective screening
– Elevated blood glucose often unrecognized
– Morbidity is usually later onset
Ganguli R. Clin Psych News, 1999;27:20
Hagg S et al. J Clin Psychiatry. 1998;59:294-299
Wirshing DA et al. Biol Psychiatry. 1998;44:778-783
Casey, DE et al, APA, May 8, 2001
Henderson DC et al. Am J Psychiatry 2000;157:975-981

58. 87% of patients taking Iloperidone did not experience
significant weight gain
Data based on pooled data
Better metabolic profile
Significant
Weight Gain
from 4 placebo-
13% controlled, 4- or 6 week
, fixed or flexible-dose
studies.
Did not Those who gain weight do
Experience
Significant it early; what happens in
Weight Gain
87%
the first three weeks are
predictive
Iloperidone Placebo
13% 4%

59. Changes in lipid profile
• Data based on pooled data from 4 placebo-controlled, 4- or
6 week , fixed or flexible-dose studies – changes in lipid is
comparable to placebo
Iloperidone Iloperidone Placebo
Median
10-16 20-24 (N=587)
change from
Better metabolic profile
mg/day mg/day
baseline
(N=483) (N=391)
(mg/dL)
Triglycerides 26.5 8.8 26.5
Total 3.9 3.9 7.7
Cholesterol

60. Percentage of patients experience
somnolence
• Data based on pooled data from 4 placebo-controlled, 4- or
6 week , fixed or flexible-dose studies
Placebo
Iloperidone ≥ 10 mg/day
(N=587)
(N=874)
11.9% 5.3%

61. Mean Change in Prolactin levels from baseline
• In pooled analysis from clinical studies including longer
term trials –
• In 3210 patients treated with Iloperidone, gynecomastia was
reported in 2 male subjects (0.1%) compared to 0% in placebo-
treated patients
• Galactorrhea was reported in 8 female subjects (0.2%) compared
to 3 female subjects (0.5%) in placebo-treated patients
Iloperidone
Placebo
24mg/day
2.6 ng/mL -6.3 ng/mL
Male 0.1% 0%
(Gynecomastia)
Female 0.2% 0.5%
(Galactorrhea)

62. Safety – Iloperidone versus haloperidol and risperidone
(hyperprolactinemia)
• Hyperprolactinemi
a is a common side
effect with Changes in prolactin levels (mcg/l)
antipsychotics 250
214.5
200
150
• Decreased levels 100
115.8 Iloperidone
Haloperidol
found in 50 Risperidone
iloperidone group 0
1
Placebo
-50
-38
-57.4
-100
• Increased levels
found in
haloperidol and
risperidone groups
J Clin Psychopharmacol 2008; 28: S12–S19

63. Cardiac safety of iloperidone
• Less QTc prolongation (2.9-9.1 msec) compared to ziprasidone (9-14
msec)
• No significant changes in blood pressure, heart rate in Indian study
• No deaths or serious arrhythmias attributable to QTc prolongation
Variable Iloperidone (n = 127) Haloperidol (n = 127)
Day 0 Day 42 2 Day 0 Day 42 2
122.77 9.92 121.74 123.89 9.66 122.03
Blood Systolic
11.68 10.70
Pressure
Diastolic 78.20 6.51 77.50 6.58 79.39 5.81 78.71 5.76
Pulse Rate 81.95 8.66 81.60 6.07 82.02 6.84 80.93 5.64
Haemoglobin 12.97 1.59 13.08 1.40 12.72 1.76 12.76 1.61
7684.92 7724.80 7500.79 7454.37
Total WBC
1680.24 1453.56 1541.77 1272.45
Total billirubin 0.77 0.17 0.78 0.16 0.77 0.16 0.75 0.16
SGOT 26.23 7.02 26.25 7.09 25.76 7.42 25.70 6.41
SGPT 22.99 6.19 23.74 7.29 24.10 6.34 24.10 5.46
Serum Creatinine 0.88 0.16 0.89 0.14 0.89 0.14 0.91 0.14

64. Dosage and administration
• Dose must be titrated slowly from a low starting dose to avoid
orthostatic hypotension
• Starting dose is 1 mg twice daily
• Increases to reach target dose range of 6 – 12 mg twice daily
may be made by with daily dose adjustments to 2 mg twice daily
• Maximum recommended dose – 24 mg/day
• Half dose should be given to poor metabolizers of CYP2D6
DAY 1 DAY 2 DAY 3 DAY 4
Take one 1-mg Take one 2-mg Take one 4-mg Take one 6-mg
tablet in the tablet in the tablet in the tablet in the
morning (AM), morning (AM), morning (AM), morning (AM),
and one 1-mg and one 2-mg and one 4-mg and one 6-mg
tablet in the tablet in the tablet in the tablet in the
evening(PM), evening(PM), evening(PM), evening(PM),
1 mg 2 mg 4 mg 6 mg
1 mg 2 mg 4 mg 6 mg

65. Target dose
Efficacious dosage strengths
6 mg twice 8 mg twice 10 mg twice 12 mg twice
daily daily daily daily
12 mg/day 16 mg/day 20 mg/day 24 mg/day
Dose 10–16 mg dose demonstrated positive treatment effects across
the multiple dimensions of psychopathology- positive, negative,
cognitive, excitement/hostility and depression/anxiety
Generally recommended that responding patients be continue beyond
acute response
Re-initiation of titration schedules should be followed whenever
patient have had interval off iloperidone for > 3 days
Efficacy of iloperidone in schizophrenia, Schizophrenia Research (2011)

66. Drug interactions
• Potent inhibitor of CYP3A4 as
ketoconazole, clarithromycin and inhibitor of CYP2D6
as fluoxetine, paroxetine increases the conc. of
iloperidone
• Reduce the dose of iloperidone to half with these
drugs
• Enhanced effect with certain antihypertensives
• It should be avoided in combination with other drugs
which prolong QTc as
quinidine, procainamide, amiodarone, sotalol, chlorpr
omazine, thioridazine, gatifloxacin, moxifloxacin etc.
• Use cautiously with alcohol

67. Precautions
• Pregnancy:- No adequate, well controlled studies available.
Should be used if potential benefit justifies potential risk to
fetus
• Lactation:- Not known whether it is excreted in breast milk, so
breast feeding should be avoided
• Pediatric use:- Safety and effectiveness in pediatric and
adolescent patient have not been established
• Elderly persons:- Vigilance should be exercised as there may be
increased risk of mortality and cerebrovascular events
• Iloperidone is not approved to use in patient with dementia
related psychosis
• Hepatic impairment:- Not recommended in hepatic impairment
• Increased risk of treatment emergent hyperglycemia related
adverse events

68. Precautions
• Fasting blood sugar should be regularly monitored in
diabetic patients on iloperidone
• Should be avoided in patient with significant cardio
vascular disease as QT prolongation, uncompensated heart
failure, recent myocardial infarction or conduction
abnormalities
• Baseline serum K & Mg measurements with periodic
monitoring should be done
• Frequent CBC monitoring should be done in patients with
pre existing low WBC count or history of drug induced
neutropenia
• Dosage adjustment are not routinely indicated on basis of
age, gender, race or renal impairment status

69. Adverse effects
• Treatment emergent adverse reactions reported in >2% patients
– Arthralgia
– Fatigue
Infrequent reactions –
– Musculoskeletal stiffness
Anemia, vertigo, tinnitus,
– Weight gain hypothyroidism, gastritis, cataract,
– Dizziness salivation, hypokalemia
– Somnolence
– Extrapyramidal symptoms
– Orthostatic hypotension
• Other frequent AEs-
– Palpitation Rare adverse reactions –
– Muscle spasm Leukopenia, arrrhythmia, AV block,
– Restlessness & aggression cardiac failure, reflux esophagitis,
menstrual irregularities,
– Urinary incontinence
gynecomastiaa
– Erectile dysfunction

70. Overdosing
• Largest single dose ingestion of iloperidone was 576mg; No
serious adverse events were seen
• In general, reported signs & symptoms were exaggeration of
known pharmacological effects as drowsiness, sedation,
tachycardia, hypotension
• No antidote for iloperidone, so supportive measures should be
instituted as securing the airway, gastric lavage, administration
of activated charcoal & laxative
• Cardiovascular monitoring including continuous ECG
monitoring to detect possible arrhythmias & QTc prolongation
• Blood pressure should be monitored
• Watch for extrapyramidal symptoms

71. PHARMACOGENOMICS
1. Whole genome association study done to evaluate efficacy, safety
and tolerability of antipsychotic, iloperidone, in patients with
schizophrenia
• Six loci of Single Nucleotide Polymorphisms (SNP) were identified
• Study of these polymorphisms and genes may lead to a better
understanding of the etiology of schizophrenia and of its treatment
2. Whole genome association study of drug-induced QT prolongation
identified DNA polymorphisms associated with QT prolongation
in six loci
• Results of this pharmacogenomic study provide new insight into
the clinical response to iloperidone, developed with the goal of
directing therapy to those patients with the optimal benefit/risk
ratio Molecular Psychiatry 14, 1024-1031 (November 2009)
Molecular Psychiatry (2009) 14, 804–819; doi:10.1038/mp.2008.56

72. Summary
• Atypical antipsychotic, structurally similar to risperidone
• Oral tablet formulation is well absorbed by GIT
• Long half life so twice daily dosing
• Metabolised by liver through CYP3A4 & CYP2D6 isozymes and
excreted in bile and feces
• Mechanism of action
• High D2 antagonism (mesolimbic area) - Resolves +ive
symptoms without EPS & prolactin increase
• High D3 antagonism – Efficacy against +ive symptoms,
reduce substance abuse , aggression
• High 5HT2a antagonism (mesocortical area)– Effectively
resolves –ive symptoms
• Moderate 5HT1A affinity – Increases GLU – enhances
cognition, resolves depression

73. Summary
• Moderate 5HT2C affinity – Resolves –ive symptoms & anxiety
• Blocks 5HT6 – Improves cognition & reduces EPS
• Blocks Alpha 1 – Modest postural hypotension, dizziness
• Blocks Alpha 2C – improves attention and cognitive function –
increases DA and NE
• Low H1 & M1 – Mild sedation, modest weight gain &
anticholinergic side effects
• Clinical studies
• Good control of over all symptoms of schizophrenia within 6
weeks (PANSS & BPRS Scale)
• Efficacy is comparable to haloperidol & risperidone
• Efficacy is also comparable to ziprasidone
• Long term efficacy is similar to haloperidol
• Lesser extrapyramidal side effects than haloperidol &
risperidone

74. Summary
• Lesser metabolic changes
• Changes in prolactin level similar to placebo
• No significant change in B.P & H.R
• Starting dose:- 1 mg/day BD, increase daily dose 2 mg
twice daily up to target dose of 6-12 mg/day
• Reduce the dose to half if given with potent inhibitors of
CYP3A4 & CYP2D6
• Avoid with other drugs which prolong QT
• Not recommended in hepatic impairment
• Safety not established in pregnancy, lactation, pediatric &
elderly demented patient
• Can be given safely in renal failure

75. PRECAUTIONS WHEN PRESCRIBING ILOPERIDONE
• Ask your patient
• If you are allergic to it
• If you are taking some other drugs
• Your medical history, especially of :
– Heart problems (as past heart attack, chest pain, abnormal heartbeat)
– Stroke
– Diabetes
– Low blood pressure
– Seizures
– Low white blood cell count
– Loss of too much body water (dehydration)
– Breast cancer
– Dementia (such as Alzheimer's Disease)
– Trouble swallowing

76. 10/10/2011
“THE GREAT PUSH : INVESTING IN MENTAL HEALTH”