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

Neurophysiology of psychotic symptoms

Social/Occupational Dysfunction - work - interpersonal relationship - self care

I. Positive Symptoms - Delusions - Hallucinations - disorganised

speech - catatonia

II. Negative Symptoms - affective flattening - alogia - avolition - anhedonia

III. Cognitive symptoms - attention - memory - executive functions

IV. Affective symptoms - dysphoria - suicidality - hopelessness

Typical (first-generation) antipsychotic drugs – mechanism of action

Improved 'positive' signs(due to blockade of excessivedopaminergic transmission inthe mesolimbic pathway)

Potential worseningof 'negative' signs(due to blockade of the already decreaseddopaminergic transmissionin the mesocortical pathway)

Extrapyramidal symptoms (due to D2 receptor blockade in nigrostriatal pathway)

Striatum

FrontalCortex

LimbicSystem

VTA Typic

alAPD

Typical

APD

TypicalAPD

D2

D2

D1D2

SubstantiaNigra

Raphe Nuclei

Serotonin secreted byserotonergic neuronscauses 5-HT2 receptorstimulation andsubsequent inhibitonof mesocorticaldopaminergicneurons

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

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

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

• 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

5HT1A receptor :- Dopamine release Glutamate release 5HT2A receptor :- Dopamine release Glutamate release

5HT2A antagonism makes antipsychotic atypical5HT2A 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

• 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

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

• 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

III. D2 Partial Agonism (DPA)

IV. 5HT1A Partial Agonism (SPA)

5HT1A receptor :- Dopamine release :-

Improves negative, cognitive & affective symptoms Improves EPS Reduces hyperprolactinemia

Glutamate release :- Reduces positive symptoms (hallucinations)

Cardiovascular risk & Antipsychotics

• H1 Histaminic receptor• 5HT2C receptor• Some antipsychotics can elevates fasting triglycerides levels and

cause insulin resistance

Weight gain

Antipsychotic Risk of weight gain

Dyslipidemia Diabetes risk

CATIE

Cardiometabolic risk

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

Increased appetite

Weightgain

Obesity Increased

BMI

Beware Cardiovasc

ular risk ahead

Triglycerides

Insulin resistance

PancreasHyperinsulinemia

Beta cell failure

Pre

diabetes

Diabetes Cardiovascular events

Premature death loss of 20-30 yrs

of normal life

Metabolic Highway

• Metabolic monitoring kit

Insulin resistance

Aging, Genes Life style, Diet Choice of antipsychotic

No option Modest chance of success Most manageable option

Baseline Visit 1 Visit 2

Wt./BMI

Fasting TGs

Fasting glucose

Blood pressure

Sedation and antipsychotics

Sedation Somnolence

M1 binding

H1 binding

Alpha binding

Alpha binding

H1 binding

Cognitive functioning

AttentionMemory

CoordinationPsychomotor activity

SleepinessDrowsiness

Need to day time sleep

Compromise overall patient functional

outcome

What constitute an ideal Antipsychotic

Ideal Antipsychotic

Mood-stabilizingproperties

Low EPS, TD

Weight Neutral

No adverseLong-term health

Consequences Affordable

Efficacious for Positive & negative

symptoms

Cognitive benefits

Improved Function andQuality of life

Limitations of Current Atypical Antipsychotics

•Gaps in efficacy remain– Cognitive function– Negative symptoms– Depressive symptoms

•Improved motor side effects but now different adverse effects for some atypicals with long-term consequences:

– Significant weight gain– Significant risk of

hyperglycemia and type 2 diabetes mellitus

– Altered lipid profile– Cardiac effects

• Hypotension• QTc prolongation

– Hyperprolactinemia

Iloperidone Pharmacology

• A benzisoxazole drug, structurally similar to risperidone

• No tricyclic structure like olanzapine, quetiapine

• Not a derivative or metabolite of other atypical antipsychotics

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

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

Iloperidone- mechanism of action (D2/5-HT2A)

• Exhibits mixed D2/5-HT2A antagonism

• Resolves – Positive symptoms – Negative symptoms– Anxiety

Expert Opin Investig Drugs 2008; 17(1): 61-75

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

D2

5HT2A

Iloperidone

D2 antagonism in mesolimbic pathway

• D2 antagonism resolves the positive symptoms

1. Stahl SM. Essential Psychopharmacology. 2nd Ed. New York, NY: Cambridge University Press; 20002. Primary Care Companion J Clin Psychiatry 2003; 5[suppl 3]: 9–13)

(1) nigrostriatal pathway (2) mesolimbic pathway (3) mesocortical pathway (4) tuberoinfundibular pathway

5-HT2A antagonism in mesocortical 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; 20002. Eur J Pharmacol. 1995 Feb 6;273(3):273-9

3. Psychopharmacology (Berl). 1998 Feb;135(4):383-91

(1) nigrostriatal pathway (2) mesolimbic pathway (3) mesocortical pathway (4) tuberoinfundibular pathway

Iloperidone- mechanism of action (D3)

• Exhibits D3 antagonism

• Resolves– Positive symptoms

1. Expert Opin Investig Drugs 2008; 17(1): 61-752. Int J Neuropsychopharmacol. 2010 Mar;13(2):181-903. Psychopharmacology (Berl). 1999 May;144(1):90-4

D 3

D2

5HT2A

Iloperidone

May also be helpful in substance abuse

aggression

Iloperidone- mechanism of action (5-HT7)

• Iloperidone exhibits 5-HT7 antagonism

• Blockade of 5-HT7 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

5HT 7D 3

D2

5HT2A

Iloperidone

Iloperidone- mechanism of action (α1)

• Iloperidone exhibits α1 receptor antagonism

• Blockade of α1 adrenoceptors helps to protect PFC cognitive function

Psychopharmacology 2004. 174(1): 25-31

5HT 7

α 1

D 3

D2

5HT2A

Iloperidone

α1 receptors in schizophrenia

• 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

High levels of norepinephrine

Activates protein kinase C (Pathway for etiology of

schizophrenia)

Impaired pre-frontal cognitive function

PatientsPatients

Blockage of α1 receptorby the α1 antagonist

Blocks activation of protein kinase C signaling

Protects pre-frontal cognitive functioning

Patients taking α1 antagonist Patients taking α1 antagonist

Iloperidone- mechanism of action (α2C)

• Iloperidone exhibits α2C antagonism

• Norepinephrine has marked influences on PFC cognitive functioning

• Blockade of the α2C receptor improve cognition and attention by enhancing catecholamine and dopamine release

1. Expert Opin Investig Drugs 2008; 17(1): 61-752. Psychopharmacology 2004. 174(1): 25-31

5HT 7

α 1

D 3

D2

5HT2A

Iloperidone

α 2C

Iloperidone- mechanism of action (5-HT2C)

• Iloperidone exhibits 5HT2C receptors antagonism

• 5-HT2C receptors 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): 242-513. Genes Brain Behav 2007; 6(5): 491-6

5HT 7

5HT 6

5HT2C

α 1

D 3

D2

5HT2A

Iloperidoneα 2C

5-HT2C receptors in anxiety

• 5-HT2C receptor antagonists alleviate anxiety via blunting of corticotropin-releasing hormone neuronal

activation in pre-frontal cortex

Sensory information

Processed inamygdala

5-HT2C receptor activation.Release of corticotrophin-

releasing hormone

Neuronal activation inprefrontal cortex

Execution function

Anxiety

Blunting of amygdala corticotropin-releasing

hormone neuronal activation

No anxiety

Iloperidone blocks 5-HT2C receptor

Genes Brain Behav 2007; 6(5): 491-6

Iloperidone- mechanism of action (5-HT1A)

• Iloperidone exhibits low 5-HT1A receptors partial agonism

• Enhances cognition by 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: 712. Behav Brain Res 2008; 195(1): 54-773. Eur J Pharmacol. 1987; 134(3): 265-74

5HT 7

5HT 6

5HT2C

5HT1A

α 1

D 3

D2

5HT2A

Iloperidoneα 2C

Activation of 5-HT1A receptor

Inhibit glutamate

Pathological alterations in the neuronal circuitry of the dorsolateral

prefrontal cortex

Impaired cognition, learning, and memory by interfering

with memory-encoding mechanisms

5-HT1A receptor in cognition

1. BMC Psychiatry. 2009;9: 712. Behav Brain Res 2008; 195(1): 54-773. Eur J Pharmacol. 1987; 134(3): 265-74

Resolves depression by increasing the dopamine release in the mPFC by postsynaptic activation of the 5-HT1A receptors

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.

Iloperidone

Clinical studies of IloperidoneEFFICACY AND SAFETY STUDIED IN MORE THAN 3000 PATIENTS

• Efficacy studied in > 3000 patients

• 4 short-term (4-6 weeks) and 3 long-term (52 weeks) studies

Expert Rev Neurother 2009; 9(12): 1727-1740

3000 -To evaluate the efficacy and safety of three fixed doses of iloperidone (4, 8and 12 mg/day) given twice daily for 42 days compared with placebo,in schizophrenia and schizoaffective patients with acute exacerbation 3001- To evaluate the efficacy and safety of iloperidone (4 -16 mg/day) given,3002 twice daily for up to 52 weeks compared with haloperidol (5 - 20 mg/day),3003 in schizophrenia and schizoaffective patients 3004 To evaluate the efficacy and safety of two dose ranges of iloperidone (4 - 8and 10 - 16 mg/day) given twice daily for 42 days compared with placebo,in schizophrenia and schizoaffective patients with acute exacerbation 3005 To evaluate the efficacy and safety of two dose ranges of iloperidone(12 - 16 and 20 - 24 mg/day) given twice daily for 42 days compared withplacebo, in schizophrenia and schizoaffective patients ‘withacute exacerbation 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, inschizophrenia patients with acute exacerbation

BETTER CONTROL OF OVERALL SYMPTOMS WITHIN 6 WEEKSIloperidone 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

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

**

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

Efficacy – Iloperidone versus haloperidol and risperidone (BPRS and PANSS-T scores)

• Iloperidone shows comparable efficacy with haloperidol, risperidone

-5.8

-3.6

-7.3

-10

-6.3

-3.7

-8.9

-11.4

-7.1

-3.6

-8.4

-11.9

-16.5

-18.8-18.9-20

-18

-16

-14

-12

-10

-8

-6

-4

-2

0

Iloperidone

Haloperidol

Risperidone

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

PANSS-T PANSS-P PANSS-N PANSS-GP BPRS

J Clin Psychopharmacol 2008; 28: S4–S11

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 positive and negative syndrome scale total scores (PANSS)

• Efficacy of iloperidone was comparable to that of ziprasidone

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• The primary efficacy: Time to

relapse, defined as a 25% or more increase in PANSS total score

• Time to relapse was similar in iloperidone and haloperidol groups as observed by hazards analysis of time to relapse

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

Safety and tolerability

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.

Iloperidone ≥ 10 mg/day(N=874)

Placebo(N=587)

5% 5%

• The type of adverse events that led to discontinuation were similar for the iloperidone and placebo-treated patients

Safety – Iloperidone versus haloperidol and risperidone (discontinuation due to AEs)

• More patients discontinued medications in the risperidone and haloperidol group compared to that in the iloperidone group due to adverse events

Adverse events leading to discontinuation of medicines

3.9

6.2

7.6

0

1

2

3

4

5

6

7

8

Pts with ≥ 1 AE leading to discontinuation (%)

Iloperidone

Risperidone

Haloperidol

J Clin Psychopharmacol 2008; 28: S4–S11

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

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)

Data based on pooled data from 4 placebo-controlled, 4- or 6 week , fixed or flexible-dose studies

Safety:- Patients taking Iloperidone experienced an incidence of EPS similar to placebo in CTs .

Does not increase with increased dose

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

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)

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

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

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

Safety - Iloperidone versus haloperidol and risperidone (dyskinesia)

• Dyskinesia items showed significant improvement from baseline in the iloperidone group

-0.1

-0.4-0.2-0.1 -0.2

0.10.2 0.2 0.2

-0.6-0.4-0.2

00.20.4

Dyskinesia Dyskinesia physician

total

Trunk limb dyskinesia

I loperidoneRisperidoneHaloperidol

• 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

Long term safety – Iloperidone versus haloperidol (overall AEs)

0

5

10

15

4.9 4 3.8 3.52.2

0.8

12.7 12.714.4

6.85.1 5.9

Adverse events (% of patients)

Iloperidone Haloperidol

J Clin Psychopharmacol 2008;28: S29–S35)

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;27:20Hagg S et al. J Clin Psychiatry. 1998;59:294-299Wirshing DA et al. Biol Psychiatry. 1998;44:778-783Casey, DE et al, APA, May 8, 2001Henderson DC et al. Am J Psychiatry 2000;157:975-981

87% of patients taking Iloperidone did not experience significant weight gain

Did not Experience Significant

Weight Gain87%

Significant Weight Gain

13%

Data based on pooled data from 4 placebo-controlled, 4- or 6 week , fixed or flexible-dose studies. Those who gain weight do it early; what happens in the first three weeks are predictive

Iloperidone Placebo

13% 4%

Bet

ter

met

abol

ic p

rofi

le

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

Median change from

baseline (mg/dL)

Iloperidone 10-16 mg/day(N=483)

Iloperidone 20-24 mg/day(N=391)

Placebo(N=587)

Triglycerides 26.5 8.8 26.5

Total Cholesterol

3.9 3.9 7.7Bet

ter

met

abol

ic p

rofi

le

Percentage of patients experience somnolence

• Data based on pooled data from 4 placebo-controlled, 4- or 6 week , fixed or flexible-dose studies

Iloperidone ≥ 10 mg/day(N=874)

Placebo(N=587)

11.9% 5.3%

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 24mg/day Placebo

2.6 ng/mL -6.3 ng/mL

Male (Gynecomastia)

0.1% 0%

Female (Galactorrhea)

0.2% 0.5%

Safety – Iloperidone versus haloperidol and risperidone (hyperprolactinemia)

• Hyperprolactinemia is a common side effect with antipsychotics

• Decreased levels found in iloperidone group

• Increased levels found in haloperidol and risperidone groups

-38

115.8

214.5

-57.4-100

-50

0

50

100

150

200

250

1

Changes in prolactin levels (mcg/l)

Iloperidone

Haloperidol

Risperidone

Placebo

J Clin Psychopharmacol 2008; 28: S12–S19

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

Blood Pressure

Systolic122.77 ± 9.92 121.74 ± 11.68 123.89 ± 9.66 122.03 ±

10.70

Diastolic 78.20 ± 6.51 77.50 ± 6.58 79.39 ± 5.81 78.71 ± 5.76Pulse Rate 81.95 ± 8.66 81.60 ± 6.07 82.02 ± 6.84 80.93 ± 5.64Haemoglobin 12.97 ± 1.59 13.08 ± 1.40 12.72 ± 1.76 12.76± 1.61

Total WBC7684.92 ± 1680.24

7724.80 ± 1453.56

7500.79 ± 1541.77

7454.37 ± 1272.45

Total billirubin 0.77 ± 0.17 0.78 ± 0.16 0.77 ± 0.16 0.75 ± 0.16SGOT 26.23 ± 7.02 26.25 ± 7.09 25.76 ± 7.42 25.70 ± 6.41SGPT 22.99 ± 6.19 23.74 ± 7.29 24.10 ± 6.34 24.10 ± 5.46Serum Creatinine 0.88 ± 0.16 0.89 ± 0.14 0.89 ± 0.14 0.91 ± 0.14

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 tablet in the morning (AM), and one 1-mg tablet in the evening(PM),

Take one 2-mg tablet in the morning (AM), and one 2-mg tablet in the evening(PM),

Take one 4-mg tablet in the morning (AM), and one 4-mg tablet in the evening(PM),

Take one 6-mg tablet in the morning (AM), and one 6-mg tablet in the evening(PM),

1 mg 2 mg 4 mg 6 mg

1 mg 2 mg 4 mg 6 mg

Efficacious dosage strengths

6 mg twice daily

8 mg twice daily

10 mg twice daily

12 mg twice daily

12 mg/day 16 mg/day 20 mg/day 24 mg/day

Targ

et

dose

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)

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, chlorpromazine, thioridazine, gatifloxacin, moxifloxacin etc.

• Use cautiously with alcohol

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

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

Adverse effects

• Treatment emergent adverse reactions reported in >2% patients– Arthralgia– Fatigue– Musculoskeletal stiffness– Weight gain– Dizziness– Somnolence– Extrapyramidal symptoms– Orthostatic hypotension

• Other frequent AEs- – Palpitation– Muscle spasm– Restlessness & aggression– Urinary incontinence– Erectile dysfunction

Infrequent reactions –Anemia, vertigo, tinnitus,

hypothyroidism, gastritis, cataract, salivation, hypokalemia

Rare adverse reactions –Leukopenia, arrrhythmia, AV block, cardiac failure, reflux esophagitis,

menstrual irregularities, gynecomastiaa

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

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

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

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

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

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

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