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newer antipsychotic iloperidone, by anant kumar rathi
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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”