Newer atypical antipsychotic agents

description of newer antipsychotic medication

1. NEWER ANTIPSYCHOTICS DR YASHASREE POUDWAL K.J.SOMAIYA HOSPITAL CONSULTANT PSYCHIATRIST

2. INTRODUCTION Antipsychotics are commonly prescribed for various psychiatric conditions like schizophrenia, BPD, depression, delirium, agitation etc. Atypical/2 nd generation antipsychotics have been criticized for their metabolic effects such as weight gain, glucose intolerance and lipid derangements. Increase risk of, as well as mortality and morbidity of diabetes mellitus and cardiovascular disease. Increase risk of CVA in patients of dementia

3. Following the publication of CATIE trials in 2005, shadow of doubt of overall effectiveness of atypicals Patients may not respond or respond incompletely Newer agents for improved antipsychotic effect, reduced rate of refractory illness and reduced metabolic and neurological side effects. Aripiprazole in 2002, relative gap in development of new drugs. Newer antipsychotics refer to drugs introduced after 2005.

4. PALIPERIDONE (INVEGA) FDA approval Schizophrenia- December 2006 Maintenance of Schizophrenia- April 2007 Acute treatment of Schizoaffective disorder ( monotherapy and adjunct to mood stabilizer/antidepressant)- July 2009 MOA Antagonist at D2-dopaminergic receptors, Alpha1-adrenegic and Alpha2-adrenergic receptors and H1-histaminergic receptors Serotonin (5-HT2A) agonist activity

5. PK/PD Major active metabolite of risperidone Absolute oral bioavailability is 28% Independent of food Steady state concentrations attained within 4-5 days Osmotic, controlled-release mechanism Extended delivery system, elimination half-life- 23hours Primarily renal metabolism. 10% hepatic metabolism. No clinically important pharmacokinetic interactions with CYP isozymes No dosage adjustment required in patients with mild-moderate hepatic impairment INDICATIONS Schizophrenia (acute and maintenance) Schizoaffective disorder ( monotherapy and adjunct)

6. DOSAGE: Sold as 1.5mg, 3mg, 6mg and 9mg ER formulation tablets and long-acting injection ( Invega Sustena ) Recommended dosage is 6mg once daily in the morning. To be increased by 3mg/day at 5 day intervals Maximum recommended dosage is 12mg/day Invega sustena : Long acting injectable formulation White aqueous suspension; extended release Strengths: 39mg, 78mg, 117mg, 156mg, 234mg-  25mg, 50mg, 75mg, 100mg and 150 mg respectively Prefilled syringe with stopper Initial injection of 234mg followed by 156mg 1 week later First 2 injections given in the deltoid (higher plasma concentration) Subsequent monthly injections can be alternated between deltoid and gluteal region

7. DOSE EQUIVALENCE: 3mg 39-78mg inj 6mg117mg inj 12mg234mg inj ADVERSE EFFECTS: Akathesia Somnolence Insomnia Parkinsonism Hyperprolactinemia Weight gain Dyslipidemia Tachycardia, increased QTc interval Dizziness, orthostatic hypotension EPS in high doses Priapism Ileus Thrombotic thrombocytopenic purpura Urinary incontinence, urinary retention

8. PRECAUTIONS: C/I if documented hypersensitivity to paliperidone or risperidone Pre-existing severe GI stenosis h/o seizures mild-moderate renal impairment Not in severe renal impairment C/I if h/o arrythmias , recent MI, CCF DRUG INTERACTIONS Co-administration with divalprovex increases concentration of paliperidone (up to 50% increase) With CBZ there is decrease in concentration of paliperidone With antihypertensive agents (orthostatic hypotension)

9. ILOPERIDONE FDA approval May 2009 for schizophrenia MOA High affinity antagonism of serotonergic (5-HT2A), Alpha1 and Alpha2c-adrenergic and D2 and D3- dopaminergic receptors INDICATIONS Reduces symptoms of acute exacerbations of schizophrenia and schizoaffective disorder. 5-week trial showed efficacy of iloperidone as maintenance therapy in reducing positive and negative symptoms ESRS scores improved and Akhathisia scores significantly reduced from baseline

10. PK/PD: Well absorbed after administration Peak plasma concentration : 2-4 hours Relative bioavailability: 96% Metabolized hepatically (CYP3A4 and CYP2D6) Renal excretion Mean elimination half life: 18-31 hours depending on whether the patient is a normal, poor or extensive metabolizer Steady state concentration: 3-4 days ADVERSE EFFECTS: Dizziness, orthostatic hypotension, sedation Dry moth, nasal congestion Weight gain: common dose dependent Dose dependent tachycardia, QTc prolongation Incidence of akhathisia comparable to placebo (Barnes Akhathisia Scale)

11. DOSAGE: Available as 1mg, 2mg, 4mg, 6mg, 8mg, 10mg, 12mg tablets Initiated at 1mg twice a day (to prevent orthostatic hypotension) Increased to 2mg, 4mg, 6mg, 8 mg, 10 mg and 12mg twice daily on subsequent days Titrated to effective dose of 12-24 mg/day over 1-2 weeks Maximum dose of 24mg/day If discontinued for >3days regimen may be needed to be restarted as the initial titration schedule for tolerability PRECAUTIONS: Anti-hypertensive agents Not to be given with drugs that prolong QTc interval ( pimozide , moxifloxacin , certain antiarrythmics ) C/I in patients with h/o cardiac arrhythmia Use in caution in patients with cardiac impairments

12. DRUG INTERACTIONS: CYP2D6 inhibitors (paroxetine, fluoxetine) : increase levels CYP3A4 inhibitors (fluvoxamine, ketoconazole, fluoxetine, nefazodone ): increase levels

13. ASENAPINE FDA approval Approved in AUGUST 2009 Treatment of schizophrenia in adults Acute treatment ( monotherapy and adjunct) for manic or mixed episode in Bipolar I disorder MOA: High affinity antagonist at 5HT1A, 5HT1B, 5HT2A, 5HT2B, 5HT2C AND 5HT5-7 serotonergic receptors; D1-D4 dopaminergic receptors; at Alpha1 and Alpha2- adrenergic receptors; and H1- histaminergic receptors Moderate antagonist affinity for histaminic H2 receptors

14. PK/PD: Sublingual administration Rapid absorption; C-max within 30-90 min Patients should not eat or drink for 10 minutes Metabolized in liver Enzyme inhibitor (CYP2D6) Mean terminal half life: 24hours Absolute bioavailability : 35% however; falls to 2% if swallowed and not dissolved Steady state attained within 3days Elimination: 90%, 50% in urine and 40% in feces ADVERSE AFFECTS: Sedation, dizziness, hypotension Somnolence Fatigue Dry mouth Oral Hypoesthesia EPS (<5%) Dyslipidemia Increased weight

15. DOSAGE: Available as 5mg, 10mg sublingual tablets Schizophrenia: Starting and target dose  5mg twice daily Max dose 10mg twice daily Bipolar Mania ( monotherapy ): Initial dose 10mg twice daily; can be decreased to 5mg BD if there are adverse effects Bipolar Mania (adjunct): Initial 5mg twice daily Can be increased to 10 mg twice daily if required PRECAUTIONS: Patients with cardiac problems No dose adjustment required in renal or mild-moderate hepatic impairment C/I in severe hepatic impairment C/I if p/h/o proven hypersensitivity Increased mortality in patients with dementia related psychosis

16. DRUG INTERACTIONS: CYP1A2 inhibitors ( fluoxamine ) can increase Asenapine levels Increases levels of Atomoxetine , Beta blockers via CYP2D6 inhibition Can antagonize dopamine agonists Anti-hypertensive agents Structurally similar to Mirtazapine and shares its pharmacological binding properties  potential in treatment resistant and bipolar depression Research currently underway for a long acting (4 week) depot formulation Need for slow titration may limit the usefulness of iloperidone in an acute setting Useful for patients who are noncompliant by way of ‘ cheeking ’ their medication

17. LURASIDONE FDA APPROVAL: October 2010 for treatment of schizophrenia 2013 for bipolar depression MOA: Potent antagonist of D2, 5HT2A, 5HT7 Partial agonist at 5HT1A 5HT7 action  procognitive effect INDICATIONS: Schizophreia Bipolar depression- monotherapy and adjunct to lithium and valproate

18. PK/PD: Low bioavailability of 9-19% Absorption affected by food; should be given with a meal of at least 350 kcal Peak serum concentration: 1-3 hours Highly protein bound Hepatic metabolism- CYP3A4 2 major active and 2 inactive metabolites Primarily excreted in feces (90%); rest in urine Mean elimination half time: 18 hours ADVERSE EFFECTS: Sedation, dizziness Orthostatic hypertension Akathisia Nausea, dyspepsia Dyslipidemia (class warning) Weight gain in short term; however in the long term patients seen to lose weight (1.5 kg avg ) Rare: seizures, NMS

19. DOSAGE: Available as 40mg, 80mg tablets (20,60,120 mg tablets available in the USA) For schizophrenia Initial dose: 40mg/day; Average dose of 80mg/day can be increased up to 160 mg/day For bipolar depression Starting dose is 20mg/day Effective dose range: 20-120mg/day Max dose limit: 120/day Once daily dosing Must be taken with food

20. PRECAUTIONS: Moderate- severe hepatic impairment: starting dose 20mg/day, max dose of 80 mg and 40mg/day Moderate-severe renal impairment: starting dose 20mg/day; max dose of 80mg/day Antihypertensive agents C/I in patients with hypersensivity ; h/o angioedema C/I in patients using strong CYP3A4 inhibitors (ketoconazole, clarithromycin, ritonavir, voriconazole ) or inducers (rifampicin, phenytoin, carbamazepine) Category B rating in pregnancy i.e. safest amongst atypical antipsychotics

21. BLONANSERIN FDA APPROVAL: Not FDA approved Approved for treatment in Japan and Korea in 2008 and 2009 respectively MOA: Blockade of D2, D3 AND 5HT2A receptors Affinity for D receptors is 6x greater than that for 5HT receptors i.e. similar to FGAs However, low affinity for 5HT2C, adrenergic a1, H1 and muscarinic M1 receptors may minimize its potential to induce certain s/e like orthostatic hypertension, over sedation, weight gain, metabolic abnormalities and peripheral anticholinergic s/e High affinity for 5HT6 receptors  likely improvement in cognition

22. INDICATIONS: S chizophrenia PK/PD: Half life; 4-10 hours Oral bioavailability: 84%; better absorption with food (2-7 fold higher) Plasma steady state conc : 5 days Rapidly absorbed from GI except stomach Metabolized by liver: CYP3A4 enzyme Excreted predominantly in urine; rest in feces

23. ADVERSE EFFECTS Overall well tolerated Lower incidence of EPS than Haloperidol, Risperidone Akathisia and tremors most common Lesser incidence of hyperprolactinemia as compared to Risperidone Sedation, orthostatic hypotension – significantly less than haloperidol/ risperidone Constipation, thirst, dizziness is seen in a small percentage of patients No significant changes in fasting glucose, cholesterol, or triglycerides have been observed ; Weight gain uncommon The incidence of QTc interval prolongation is seen to be very low Dangerous AE Increased risk of death and CVA in elderly patients with dementia related psychosis Rare : seizures, NMS

24. DOSAGE Initial dose : 4mg twice daily Maintenance dose : 8-16 mg/day Max : 24 mg/day Available as 2mg, 4mg and 8mg tablets To be administered strictly after meals PRECAUTIONS Hepatic impairment Concurrently with CYP3A4 inhibitors (e.g.. Ketoconazole) May worsen suicidal ideation Contraindicated in patients with altered sensorium, hypersensitivity Concurrently with CNS depressants

25. Studies show Blonanserin to be as effective as Haloperidol and Risperidone in treatment of positive symptoms More effective than Haloperidol wrt negative symptoms Improved certain cognitive functions associated with prefrontal cortical functioning i.e. attention, letter fluency) Further large-scale long-term trials comparing Blonanserin with other SGAs, are warranted to establish its efficacy, safety, and effectiveness for the treatment of schizophrenia.

26. CARIPRAZINE FDA APPROVAL: September 2015 Approved for schizophrenia and bipolar mood disorder MOA: Partial agonist at D3 and D2 receptors and 5HT1A receptors Preference for D3 receptors may improve cognition, mood and negative symptoms INDICATIONS: Schizophrenia Bipolar mood disorder: both manic and mixed episodes

27. PK/PD: Activity mediated by parent drug and 2 major active metabolites (equipotent at target receptors) Steady state: 1-2 weeks; 4-8 weeks Mean half life:2-5 days, however metabolites have considerably longer half life Gradual increase in activity and active moiety likely to remain in plasma for longer duration Hepatic metabolism ADVERSE EFFECTS: Akathisia Metabolic changes

28. DOSING: Available as 1.5mg, 3mg, 4.5mg,6mg capsules Once daily dosing Starting dose: 1.5mg/day increased to 3-6mg/day

29. BREXIPRAZOLE FDA APPROVAL: July 2015- schizophrenia & major depression 2016- maintenance treatment of schizophrenia MOA: 5HT1A AND D2 partial agonist Developed as its predecessor aripiprazole , with reduced tendency to cause akathisia,restlessness and insomnia INDICATIONS: Schizophrenia- acute and maintenance treatment Major depressive disorder- adjunct

30. PK/PD: Peak plasma concentration: 4 hours Steady state concentration: 10-12 days Hepatic metabolism Excreted in feces and urine ADVERSE EFFECTS: Metabolic changes EPS and Akathisia Nausea Blurred vision Hyperprolactinemia Sleep disturbance (somnolence, insomnia)

31. DOSING: Available as 0,25, 0.5, 1,2 3 and 4 mg tablets Schizophrenia: Started on 1mg/day; increased to 2mg after 3 days 4 mg if necessary Rec dose range: 2-4 mg Depression: Started at 0.5-1mg/day Rec dose 2mg/day

32. OTHER NOVEL ANTIPSYCHOTICS Interest in developing a antipsychotic that are not dopamine antagonists with limited progress Pomaglumetad , agonist metabotropic glutamate rec 2 and 3 (failed later trials) Sarcosine , inhibits the glycine transporter (GlyT-1) Biopterin , also GlyT-1 inhibitor, not effective Pimaverin , inverse agonist of 5HT2A; possible adjuvant Phosphodiesterase inhibitors- being studied for antipsychotic effects

33. REFERENCES Kaplan and Saddock’s Comprehensive Textbook of Psychiatry. Tenth Edition Jonathan R Scarff and David A Casey; Newer Oral Antipsychotics: A Review Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3 rd Edition Invega tablets, prescribing information: Ortho-McNeil-Janssen Pharmaceuticals Inc.; 2007 Rockville, Md.: Vanda Pharmaceuticals, Inc.; Aug, 2010. Fanapt ( iloperidone ), prescribing information . Cutler AJ, Kalali AH, Weiden PJ, et al. Four-week, double-blind, placebo- and ziprasidone -controlled trial of iloperidone in patients with acute exacerbations of schizophrenia. J Clin Psychopharmacol . 2008;28(2 Suppl 1):S20– S28 Kenilworth, N.J.: Organon ; Aug, 2009. Saphris ( asenapine maleate) sublingual tablets, prescribing information . Marlborough, Mass.: Sunovion Pharmaceuticals; Oct, 2010. Latuda ( lurasidone HCl ) tablets, prescribing information.

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