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Iloperidone
 

Iloperidone

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newer antipsychotic iloperidone, by anant kumar rathi

newer antipsychotic iloperidone, by anant kumar rathi

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    Iloperidone Iloperidone Presentation Transcript

    • ROLE OF ILOPERIDONE INPSYCHIATRIC 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
    • I. Positive II. Negative Symptoms Symptoms - Delusions - affective flattening - Hallucinations - alogia - disorganised - avolition speech - anhedonia - catatonia Social/Occupational Dysfunction - work - interpersonal relationship - self careIII. Cognitive symptoms IV. Affective symptoms- attention - dysphoria - suicidality- memory - hopelessness- executive functions
    • 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
    • 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 release5HT2A antagonism makes antipsychotic atypical 5HT2A receptor brake, on dopamine release is disrupted by 5HT2A antagonist thus increasing dopamine release in prefrontal cortex5HT2A antagonism reduces EPS5HT2A 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 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
    • 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 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
    • 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 TriglyceridesIncreased appetite Beware Cardiovasc ular risk Weight ahead gain
    • • 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
    • Sedation and antipsychotics Sedation Somnolence M1 H1 Alpha H1 Alphabinding binding binding binding binding Cognitive functioning Sleepiness Attention Drowsiness Memory Need to day time Coordination sleep Psychomotor activity Compromise overall patient functional outcome
    • What constitute an ideal Antipsychotic Mood-stabilizing Efficacious for propertiesPositive & negative Low EPS, TD symptomsCognitive benefits Ideal Weight Neutral Antipsychotic Improved No adverse Function and Long-term health Quality of life Consequences Affordable
    • 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 profilebut now different adverse – Cardiac effectseffects for some atypicals • Hypotensionwith long-term • QTc prolongationconsequences: – 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 Iloperidone antagonism • Resolves – Positive symptoms – Negative symptoms – AnxietyIt is proposed that the efficacy of iloperidone is mediatedthrough a combination of dopamine type 2 (D2) andserotonin type 2 (5-HT2A) antagonisms Expert Opin Investig Drugs 2008; 17(1): 61-75
    • 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)
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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 viablunting of corticotropin-releasing hormone neuronal activation in pre-frontal cortex Genes Brain Behav 2007; 6(5): 491-6
    • 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
    • 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
    • Iloperidone binding affinity - Summary Affinity Receptor Clinical advantageHigh 5-HT2A Improves negative symptoms and reduces anxiety D2 Improves positive symptoms D3 Improves positive symptoms. Reduces substance abuseModerate 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 anxietyLow 5-HT1A Improves cognition and resolves depression Expert Opin. Investig. Drugs 2008; 17(1): 61-75.
    • Iloperidone
    • 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
    • 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 WEEKSIloperidone 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 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
    • 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
    • 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
    • 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. PlaceboIloperidone ≥ 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
    • 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
    • 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)
    • Safety:- Patients taking Iloperidone experienced an incidence of EPS similar to placebo in CTs . Does not increase with increased doseData based on pooled data from 4 placebo-controlled, 4- or 6 week , fixed or flexible-dose studies
    • 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 0.4 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
    • 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)
    • 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
    • 87% of patients taking Iloperidone did not experience significant weight gain Data based on pooled dataBetter 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%
    • 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 fromBetter 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
    • Percentage of patients experience somnolence• Data based on pooled data from 4 placebo-controlled, 4- or 6 week , fixed or flexible-dose studies PlaceboIloperidone ≥ 10 mg/day (N=587) (N=874) 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 Placebo 24mg/day 2.6 ng/mL -6.3 ng/mLMale 0.1% 0%(Gynecomastia)Female 0.2% 0.5%(Galactorrhea)
    • 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
    • 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
    • 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
    • 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)
    • 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
    • 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 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
    • 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
    • PHARMACOGENOMICS1. 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 treatment2. 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 Alzheimers Disease) – Trouble swallowing
    • 10/10/2011“THE GREAT PUSH : INVESTING IN MENTAL HEALTH”